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Journal articles on the topic 'Allogeneic grafts'
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1
Widner, Håkan, and Patrik Brundin. "Sequential Intracerebral Transplantation of Allogeneic and Syngeneic Fetal Dopamine-Rich Neuronal Tissue in Adult Rats: Will the First Graft be Rejected?" Cell Transplantation 2, no. 4 (July 1993): 307–17. http://dx.doi.org/10.1177/096368979300200413.
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The immune response against intracerebral grafts of allogeneic fetal dopamine-rich tissue was assessed in adult rats. Sprague-Dawley rats, now outbred, but originating from an inbred stock, were given unilateral 6-hydroxy-dopamine lesions of the mesostriatal pathway, and grafted intrastriatally with mechanically dissociated ventral mesencephalic tissue (embryonic day 13-15) obtained from an inbred Lewis strain. Graft survival was assessed by functional recovery of amphetamine-induced rotational behavior on four different occasions postsurgery, and histologically using catecholamine histofluorescence and tyrosine hydroxylase immunohistochemistry. The following groups were analysed: long-term survival of a single allogeneic graft; survival of a first allogeneic graft with a syngeneic second graft; survival of a first allograft combined with a second allogeneic graft; the survival of bilateral allogeneic grafts following a subsequent orthotopic allogeneic skin graft. Evidence for recipient immunization was obtained using an indirect fluorescent antibody detection technique, Simonsen's Spleen Index (S I) test. Viable grafts, giving rise to behavioral compensation, were present after 40 wk in rats from all groups. The “first” allograft always displayed good survival and function, even following a second intracerebral allograft. However, five of nine “second” allogeneic intracerebral grafts survived poorly. In contrast, all secondary syngeneic grafts survived well. Following the application of a subsequent orthotopic allogeneic skin graft in a subgroup of rats, there was a significantly lower survival of grafted dopamine neurons in the “first” graft.
2
Zhao, Shanshan, Dai Shi, Chen Su, Wen Jiang, Chao Zhang, Ting Liang, and Guihua Hou. "IL-27Rα: A Novel Molecular Imaging Marker for Allograft Rejection." International Journal of Molecular Sciences 21, no. 4 (February 15, 2020): 1315. http://dx.doi.org/10.3390/ijms21041315.
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Non-invasively monitoring allogeneic graft rejection with a specific marker is of great importance for prognosis of patients. Recently, data revealed that IL-27Rα was up-regulated in alloreactive CD4+ T cells and participated in inflammatory diseases. Here, we evaluated whether IL-27Rα could be used in monitoring allogeneic graft rejection both in vitro and in vivo. Allogeneic (C57BL/6 donor to BALB/c recipient) and syngeneic (BALB/c both as donor and recipient) skin grafted mouse models were established. The expression of IL-27Rα in grafts was detected. The radio-probe, 125I-anti-IL-27Rα mAb, was prepared. Dynamic whole-body phosphor-autoradiography, ex vivo biodistribution and immunofluorescence staining were performed. The results showed that the highest expression of IL-27Rα was detected in allogeneic grafts on day 10 post transplantation (top period of allorejection). 125I-anti-IL-27Rα mAb was successfully prepared with higher specificity and affinity. Whole-body phosphor-autoradiography showed higher radioactivity accumulation in allogeneic grafts than syngeneic grafts on day 10. The uptake of 125I-anti-IL-27Rα mAb in allogeneic grafts could be almost totally blocked by pre-injection with excess unlabeled anti-IL-27Rα mAb. Interestingly, we found that 125I-anti-IL-27Rα mAb accumulated in allogeneic grafts, along with weaker inflammation earlier on day 6. The high uptake of 125I-anti-IL-27Rα mAb was correlated with the higher infiltrated IL-27Rα positive cells (CD3+/CD68+) in allogeneic grafts. In conclusion, IL-27Rα may be a novel molecular imaging marker to predict allorejection.
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Hyc, Anna, Jacek Malejczyk, Anna Osiecka, and Stanislaw Moskalewski. "Immunological Response against Allogeneic Chondrocytes Transplanted into Joint Surface Defects in Rats." Cell Transplantation 6, no. 2 (March 1997): 119–24. http://dx.doi.org/10.1177/096368979700600205.
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Rat chondrocytes isolated from the articular–epiphyseal cartilage complex were transplanted into defects prepared in articular cartilage and subchondral bone. Transplants were taken for examination after 3 and 8 wk. Cartilage formed by syngeneic chondrocytes did not evoke formation of infiltrations. Contrary to that, in the vicinity of cartilage produced by allogeneic chondrocytes numerous infiltrating cells were present and cartilage resorption could be observed. Cyclosporine-A (CsA) treatment of recipients of allogeneic chondrocytes only partially suppressed accumulation of infiltrating cells and matrix resorption. Antichondrocyte immune response of chondrocyte graft recipients was studied by evaluation of spleen mononuclear cells (SMC) stimulation in mixed splenocytechondrocyte cultures and by evaluation of antichondrocyte cytotoxic antibodies. No difference in stimulation of SMC from intact rats by syngeneic and allogeneic chondrocytes was observed. Stimulation by allogeneic chondrocytes was slightly but significantly higher in recipients of syngeneic grafts. SMC of allogenic chondrocyte recipients were strongly stimulated by allogeneic chondrocytes. This response was absent in recipients treated with CsA. Spontaneous antichondrocyte cytotoxic antibody activity was detected in intact rats and in recipients of syngeneic grafts. In recipients of allogeneic chondrocytes the antibody response against allogeneic chondrocytes was raised but was statistically not significant owing to the considerable variation in the level of spontaneously occurring antichondrocyte antibodies.
4
Mahan, KT, and HJ Hillstrom. "Bone grafting in foot and ankle surgery. A review of 300 cases." Journal of the American Podiatric Medical Association 88, no. 3 (March 1, 1998): 109–18. http://dx.doi.org/10.7547/87507315-88-3-109.
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Three hundred foot and ankle bone grafts were reviewed in three separate series of 100 consecutive grafts from two institutions. The series represent a period from 1977 to 1990 and demonstrate treatment patterns that varied over time and between institutions in indications, graft material, and perioperative management. Over 42% of the 300 grafts were for calcaneal osteotomies; most were Evans calcaneal osteotomies. Over 72% of the grafts were allogeneic bone-bank bone, which performed well in calcaneal osteotomies and for packing of defects. Upon review of the incidence of bone complications, no significant differences were observed between surgical procedures that used autogenous versus allogeneic grafts. However, four out of six failures of first metatarsal repair were with allogeneic bone. There was a significant difference in complication rates for the major indications for bone-graft surgery. Nonunions and arthrodeses resulted in higher complication rates than expected, whereas calcaneal osteotomies resulted in a lower complication rate than expected.
5
Wallowy, Phillip, and Andreas Dorow. "Lateral Augmentation of the Maxilla and Mandible Using Framework Technique With Allogeneic Bone Grafts." Journal of Oral Implantology 38, no. 6 (December 1, 2012): 661–67. http://dx.doi.org/10.1563/aaid-joi-d-11-00073.
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This study aimed to evaluate the effectiveness of lateral ridge augmentation in 36 patients with severely atrophic alveolar ridge using allogeneic bone grafts in a framework technique. A thinned allogeneic cortical graft was screwed to the alveolar ridge, leaving a hollow space that was filled with particulated allogeneic cortical bone. Thirty-six patients who received surgical lateral block augmentation using allogeneic bone grafts were involved in this study. Implants were placed in a second session after a mean time of 6.3 months. The surgical technique and the reasons for failure of surgery in three patients are described. Additionally, properties of allogeneic bone grafts are reviewed. In 33 patients, dental implants were successfully installed and continued to be well maintained at the last follow-up (91.7% success). In three patients, dental implants could not be installed (8.3% failure) as the graft was lost because of wound dehiscence; however, repeat surgery was successfully carried out in all three. The use of allogeneic bone grafts in lateral ridge augmentation of the maxilla and mandible showed successful clinical results. It seems to be a reliable material for reconstructing a severely atrophic alveolar ridge. It presents a good alternative to autogenous bone regarding augmentation because it offers good ossification, less morbidity, unlimited availability and shorter duration of surgery, and lower costs.
6
Mellonig, James T. "Autogenous and Allogeneic Bone Grafts in Periodontal Therapy." Critical Reviews in Oral Biology & Medicine 3, no. 4 (July 1992): 333–52. http://dx.doi.org/10.1177/10454411920030040201.
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This article is limited to a review of bone autografts and allografts, as used in periodontal therapy. The various graft materials are discussed with respect to case reports, controlled clinical trials, and human histology. Other reviewed areas are wound healing with periodontal bone grafts, tissue banking and freeze-dried bone allografts, and the use of bone grafts in guided tissue regeneration.
7
Monje, Alberto, Michael A. Pikos, Hsun-Liang Chan, Fernando Suarez, Jordi Gargallo-Albiol, Federico Hernández-Alfaro, Pablo Galindo-Moreno, and Hom-Lay Wang. "On the Feasibility of Utilizing Allogeneic Bone Blocks for Atrophic Maxillary Augmentation." BioMed Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/814578.
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Purpose. This systematic review was aimed at assessing the feasibility by means of survival rate, histologic analysis, and causes of failure of allogeneic block grafts for augmenting the atrophic maxilla.Material and Methods. A literature search was conducted by one reviewer in several databases. Articles were included in this systematic review if they were human clinical trials in which outcomes of allogeneic bone block grafts were studied by means of survival rate. In addition other factors were extracted in order to assess their influence upon graft failure.Results. Fifteen articles fulfilled the inclusion criteria and subsequently were analyzed in this systematic review. A total of 361 block grafts could be followed 4 to 9 months after the surgery, of which 9 (2.4%) failed within 1 month to 2 months after the surgery. Additionally, a weighed mean 4.79 mm (95% CI: 4.51–5.08) horizontal bone gain was computed from 119 grafted sites in 5 studies. Regarding implant cumulative survival rate, the weighed mean was 96.9% (95% CI: 92.8–98.7%), computed from 228 implants over a mean follow-up period of 23.9 months. Histologic analysis showed that allogeneic block grafts behave differently in the early stages of healing when compared to autogenous block grafts.Conclusion. Atrophied maxillary reconstruction with allogeneic bone block grafts represents a reliable option as shown by low block graft failure rate, minimal resorption, and high implant survival rate.
8
Aydin, Cemalettin, Volkan Ince, Emrah Otan, Sami Akbulut, Cemalettin Koc, Cuneyt Kayaalp, and Sezai Yilmaz. "Storage of Allogeneic Vascular Grafts: Experience From a High-Volume Liver Transplant Institute." International Surgery 98, no. 2 (May 1, 2013): 170–74. http://dx.doi.org/10.9738/intsurg-d-12-00035.1.
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Abstract Allogeneic vascular grafts are often required for vascular reconstruction during living donor liver transplantation. Such grafts are obtained prior to use, making storage conditions a critical issue for maintaining the integrity of the tissue to ensure a successful transplantation. This study describes an optimized storage protocol currently in use at a high-volume liver transplant center. Twenty-nine allogeneic vascular graft tissues obtained during cardiovascular surgery or from cadaveric donors were stored respectively in sterile 50 mL of Ringer lactate solution, without any preservation solutions or antimicrobials, at −22°C for a maximum of 3 months. Prior to use in vascular reconstruction, grafts were thawed in 0.9% NaCl solution at 37°C, and 1 × 0.5-cm2 tissue samples were collected for microbial culturing and viral serology. ABO compatibility was not performed for any patients receiving vascular grafts. During this prospective study, all 29 allogeneic vascular grafts were used for back-table vascular reconstruction in living donor liver transplantation procedures. A total of 16 grafts were from the saphenous vein, 10 were from the iliac vein, and 3 were from the iliac artery. Bacterial growth was not detected in any tissue samples taken from the stored grafts. No vascular graft-related complications occurred during the 5 months of follow-up. The successful vascular reconstructions achieved with all 29 study grafts demonstrate that the simple, inexpensive storage method described herein is feasible and safe. Randomized, controlled studies should be carried out to further optimize and standardize the technique.
9
Glass, Bertram, Lutz Uharek, Matthias Zeis, Peter Dreger, Helmut Löffler, Jörg Steinmann, and Norbert Schmitz. "Allogeneic Peripheral Blood Progenitor Cell Transplantation in a Murine Model: Evidence for an Improved Graft-Versus-Leukemia Effect." Blood 90, no. 4 (August 15, 1997): 1694–700. http://dx.doi.org/10.1182/blood.v90.4.1694.
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Abstract Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 × 109 nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 × 108v 1.4 × 108/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 × 109/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.
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Glass, Bertram, Lutz Uharek, Matthias Zeis, Peter Dreger, Helmut Löffler, Jörg Steinmann, and Norbert Schmitz. "Allogeneic Peripheral Blood Progenitor Cell Transplantation in a Murine Model: Evidence for an Improved Graft-Versus-Leukemia Effect." Blood 90, no. 4 (August 15, 1997): 1694–700. http://dx.doi.org/10.1182/blood.v90.4.1694.1694_1694_1700.
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Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 × 109 nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 × 108v 1.4 × 108/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 × 109/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.
11
Jones, RJ, RF Ambinder, S. Piantadosi, and GW Santos. "Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation." Blood 77, no. 3 (February 1, 1991): 649–53. http://dx.doi.org/10.1182/blood.v77.3.649.649.
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Abstract The existence of an immunologic antileukemia reaction associated with allogeneic bone marrow transplantation (BMT) is well established. However, a similar graft-versus-tumor effect against lymphomas has not been demonstrated. We analyzed the results of BMT in 118 consecutive patients with relapsed Hodgkin's disease or aggressive non-Hodgkin's lymphoma. The 38 patients less than 50 years of age with HLA-matched donors had allogenic marrow transplants, and the other 80 patients received purged autologous grafts. The median age was 26 years in both the allogeneic and the autologous graft recipients. The patient's response to conventional salvage therapy before transplant was the only factor that influenced the event-free survival after BMT (P less than .001). Both the patient's response to salvage therapy before BMT (P less than .001) and the type of graft (P = .02) significantly influenced the probability of relapse after BMT. The actuarial probability of relapse in patients who responded to conventional salvage therapy before BMT was only 18% after allogenic BMT compared with 46% after autologous BMT. However, the actuarial probability of event-free survival at 4 years was the same, 47% versus 41%, for patients with responsive lymphomas who received allogeneic and autologous transplants, respectively (P = .8). The beneficial antitumor effect of allogeneic BMT was offset by its higher transplant-related mortality (P = .01), largely resulting from graft-versus-host disease. Allogeneic BMT appears to induce a clinically significant graft-versus- lymphoma effect. The magnitude of this effect is similar to that reported against leukemias.
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Jones, RJ, RF Ambinder, S. Piantadosi, and GW Santos. "Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation." Blood 77, no. 3 (February 1, 1991): 649–53. http://dx.doi.org/10.1182/blood.v77.3.649.bloodjournal773649.
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The existence of an immunologic antileukemia reaction associated with allogeneic bone marrow transplantation (BMT) is well established. However, a similar graft-versus-tumor effect against lymphomas has not been demonstrated. We analyzed the results of BMT in 118 consecutive patients with relapsed Hodgkin's disease or aggressive non-Hodgkin's lymphoma. The 38 patients less than 50 years of age with HLA-matched donors had allogenic marrow transplants, and the other 80 patients received purged autologous grafts. The median age was 26 years in both the allogeneic and the autologous graft recipients. The patient's response to conventional salvage therapy before transplant was the only factor that influenced the event-free survival after BMT (P less than .001). Both the patient's response to salvage therapy before BMT (P less than .001) and the type of graft (P = .02) significantly influenced the probability of relapse after BMT. The actuarial probability of relapse in patients who responded to conventional salvage therapy before BMT was only 18% after allogenic BMT compared with 46% after autologous BMT. However, the actuarial probability of event-free survival at 4 years was the same, 47% versus 41%, for patients with responsive lymphomas who received allogeneic and autologous transplants, respectively (P = .8). The beneficial antitumor effect of allogeneic BMT was offset by its higher transplant-related mortality (P = .01), largely resulting from graft-versus-host disease. Allogeneic BMT appears to induce a clinically significant graft-versus- lymphoma effect. The magnitude of this effect is similar to that reported against leukemias.
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Shen, Kezhen, Shu-Sen Zheng, Ogyi Park, Hua Wang, Zhaoli Sun, and Bin Gao. "Activation of innate immunity (NK/IFN-γ) in rat allogeneic liver transplantation: contribution to liver injury and suppression of hepatocyte proliferation." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 4 (April 2008): G1070—G1077. http://dx.doi.org/10.1152/ajpgi.00554.2007.
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Liver transplantation is presently the only curative treatment for patients with end-stage liver disease. However, the mechanisms underlying liver injury and hepatocyte proliferation posttransplantation remain obscure. In this investigation, liver injury and hepatocyte proliferation in syngeneic and allogeneic animal models were compared. Male Lewis and Dark Agouti (DA) rats were subjected to orthotopic liver transplantation (OLT). Rat OLT was performed in syngeneic (Lewis-Lewis) and allogeneic (Lewis-DA or DA-Lewis) animal models. Allogeneic liver grafts exhibited greater injury and cellular apoptosis than syngeneic grafts but less hepatocyte proliferation after OLT. Expression of IFN-γ mRNA and activation of the downstream signal transducer and activator of transcription 1 (STAT1) and genes (interferon regulatory factor-1 and cyclin-dependent kinase inhibitor p21 CDKN1A) were also greater in the allogeneic grafts compared with the syngeneic grafts. In contrast, STAT3 activation was lower in the allogeneic grafts. Furthermore, in the allogeneic grafts, depletion of natural killer (NK) cells decreased IFN-γ/STAT1 activation but enhanced hepatocyte proliferation. These findings suggest that, compared with syngeneic transplantation, innate immunity (NK/IFN-γ) is activated after allogeneic transplantation, which likely contributes to liver injury and inhibits hepatocyte proliferation.
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Midha, Rajiv, Susan E. Mackinnon, Peter J. Evans, Timothy J. Best, Gregory M. T. Hare, Dan A. Hunter, and Judy A. Falk-Wade. "Comparison of regeneration across nerve allografts with temporary or continuous cyclosporin A immunosuppression." Journal of Neurosurgery 78, no. 1 (January 1993): 90–100. http://dx.doi.org/10.3171/jns.1993.78.1.0090.
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✓ The efficacy of short-term immunosuppression in a nerve allograft model was examined by comparing regeneration across peripheral nerve allografts with either temporary (12 weeks) or continuous (30 weeks) cyclosporin A treatment. One-hundred fifty Lewis rats received 2-cm nerve grafts from allogeneic ACI or syngeneic Lewis rat donors and were allocated to the following groups: allogeneic grafts and continuous cyclosporin A, with 18 weeks (20 rats) or 30 weeks (20 rats) of survival after graft placement; allogeneic grafts and temporary cyclosporin A, with 12 weeks (10 rats), 18 weeks (20 rats), or 30 weeks (20 rats) of survival; and control rats with allogeneic and syngeneic grafts, no cyclosporin A, with 12, 18, or 30 weeks (10 rats each) of survival. Functional regeneration across the nerve grafts was serially assessed with walking-track analysis. Endpoint evaluations included electrophysiological, histological, and morphometric studies. Both walking-track and electrophysiological function reached a plateau at a significantly worse level in nonimmunosuppressed allograft recipients than in syngeneic or treated allograft recipients. The group with temporary therapy experienced significant worsening in both motor and electrophysiological function at Week 18, 6 weeks after cyclosporin A withdrawal, compared to the group with continuous treatment. At Week 30, motor and electrophysiological function in the temporary-treatment group recovered to levels similar to those of the syngeneic and continuous cyclosporin A groups. Histological assessment of the graft segments from the temporary cyclosporin A group at 18 weeks showed evidence of rejection, with mononuclear cell infiltration and demyelination; morphometric evaluation demonstrated significantly decreased numbers of nerve fibers in the distal host segment. These histological and morphometric changes were no longer present in the nerves from the temporarily immunosuppressed rats at Week 30. Withdrawal of immunosuppression after successful regeneration through nerve allografts results in short-term graft rejection. Eventual restoration of graft histological and function parameters is comparable to continuously immunosuppressed rats. Temporary immunosuppression of nerve allograft recipients is feasible.
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Yunusov, Murad Y., Kraig Abrams, Christian S. Kuhr, Rainer Storb, Billanna Hwang, George E. Sale, Barry Storer, George E. Georges, and Richard A. Nash. "Donor-Specific Tolerance Is Induced after Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation and May Persist after Graft Rejection." Blood 106, no. 11 (November 16, 2005): 5230. http://dx.doi.org/10.1182/blood.v106.11.5230.5230.
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Abstract The association between stable hematopoietic chimerism and donor specific tolerance (DST) for solid organ grafts was demonstrated clinically and in different experimental models. However, the existing data also demonstrate that the establishment of hematopoietic chimerism does not always correlate with the development of DST, especially for skin grafts. As these issues could have major implications for organ transplantation in general, the present study was undertaken to assess DST in recipients with transient or stable hematopoietic cell (HC) chimerism established after nonmyeloablative conditioning regimens. In a canine model of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning, DST to skin grafts was evaluated in DLA-identical recipients with stable mixed hematopoietic chimerism (MC) (n=11), or following transient HC engraftment (n=22). There was a significant improvement in the survival of DLA-identical HC donor-derived skin grafts in recipients with stable MC compared to normal recipients (n=7; P<0.0001). However, HC donor-derived skin grafts in 4 recipients with MC developed an inflammatory reaction without skin graft loss consistent with a chronic rejection process. Survival of DLA-identical HC donor-derived skin grafts was also significantly prolonged in recipients after transient HC engraftment compared to normal recipients (P=0.002). However, a chronic inflammatory process without graft loss developed in all of the HC donor-derived skin grafts from this group. An increased time to rejection of the hematopoietic graft was significantly associated with an improved survival of the subsequent skin graft (P=0.02). The time to rejection of third-party (DLA-nonidentical) skin grafts (n=40) was the same in recipients with stable MC and previous HC graft as well as normals (median- 8 days). Autologous skin grafts (n=40) survived for the duration of follow-up without developing chronic inflammation. Extended HC donor-specific skin graft survival (>15 days) was predictive of subsequent stable engraftment at second HCT in recipients with previous graft rejection after first HCT. Five of 6 dogs with extended survival of the skin graft beyond day 15 became stable MC after second HCT compared to 0/9 dogs with skin grafts surviving less than 11 days (P=0.0008). In this model, DST to skin grafts in recipients with stable MC after nonmyeloablative HCT may not be complete, and chronic inflammation may develop without loss of that graft. Partial DST may persist after rejection of HC grafts established with nonmyeloablative conditioning. Further investigations are required to understand the mechanisms responsible for DST after allogeneic HCT.
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Blazar, BR, PA Taylor, S. Smith, and DA Vallera. "Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts." Blood 85, no. 3 (February 1, 1995): 842–51. http://dx.doi.org/10.1182/blood.v85.3.842.bloodjournal853842.
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Studies in mice and humans have indicated that the predominance of interleukin-4 (IL-4)- and IL-10-producing T-helper type 2 (Th2) cells may serve to downregulate acute graft-versus-host disease (GVHD) reactions, whereas IL-2-producing Th1 cells have been implicated in facilitating acute GVHD. We explored the possibility that the in vivo infusion of IL-10 would inhibit acute GVHD induced by fully allogeneic donor grafts. Unexpectedly, IL-10 infusions resulted in a dose- dependent increase in GVHD-induced mortality. The acceleration of lethal GVHD by IL-10 occurred in irradiated recipients of T-cell- depleted bone marrow (BM) plus 5, 15, or 25 x 10(6) splenocytes but did not influence the post-BM transplantation (post-BMT) survival rate of recipients of BM without splenocytes, suggesting that the IL-10 effects were not due to toxicity. Antimurine IL-10-neutralizing monoclonal antibody injections, administered to diminish endogenous IL-10, reduced GVHD-associated mortality and improved the clinical appearance of the recipients. For BM graft rejection studies, IL-10 was infused into sublethally irradiated recipients of anti-Thy 1.2 + C′ T-cell-depleted, fully allogeneic BM grafts. In a short-term (day 7) in vivo assay, IL- 10 infusions significantly inhibited allogeneic (but not syngeneic) BM proliferation in vivo, indicative of increased graft rejection. In long- term chimerism experiments, IL-10 infusions caused a significant increase in early post-BMT mortality caused by a profound anemia typically associated with graft rejection and aplasia. A slightly higher irradiation dose (650 cGy v 600 cGy) eliminated the anemia but did not reverse the graft rejection process associated with IL-10 administration. We conclude that the in vivo infusion of exogenous IL- 10 in recipients of fully allogeneic donor grafts results in accelerated GVHD and graft rejection in the strain combinations tested to date.
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Storb, R., RF Raff, FR Appelbaum, FW Schuening, BM Sandmaier, TC Graham, and ED Thomas. "What radiation dose for DLA-identical canine marrow grafts? [published erratum appears in Blood 1989 Feb;73(2):624]." Blood 72, no. 4 (October 1, 1988): 1300–1304. http://dx.doi.org/10.1182/blood.v72.4.1300.1300.
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Abstract In view of reported attempts at marrow grafting after nuclear accidents with a broad range of radiation exposures, the present study explored the total-body irradiation (TBI) conditions needed for engraftment in a canine model by using marrow from DLA-identical littermates. Previous studies have shown that such grafts are consistently successful when recipients are exposed to 920 cGy of TBI delivered at a rate of 7 cGy/min from opposing dual cobalt sources. The present TBI doses were all in the lethal range. Five dogs were administered 450 cGy; seven dogs, 600 cGy; five dogs, 700 cGy; and five dogs, 800 cGy of TBI administered at 7 cGy/min. They received a median of 3.3 x 10(8) marrow cells/kg intravenously after completion of radiation. Results showed transient allogeneic marrow engraftment in all dogs administered the lowest dose of TBI studied (450 cGy). Importantly, transient grafts permitted four of five dogs to live long enough for autologous marrow recovery to occur. At increasing radiation doses, 600, 700, and 800 cGy, the risk of graft failure lessened, with 3 of 7, 2 of 5, and 1 of 5 dogs, respectively, showing graft rejection. Fewer dogs survived with autologous marrow recovery, and more showed sustained allogeneic engraftment (4 of 7, 3 of 5, and 4 of 5 dogs, respectively). We conclude that DLA-identical littermate marrow grafts are beneficial in the setting of otherwise lethal radiation exposures, with most dogs either experiencing sustained allogeneic engraftment or surviving with autologous marrow recovery due to the extended support provided by a transient allogeneic graft.
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Storb, R., RF Raff, FR Appelbaum, FW Schuening, BM Sandmaier, TC Graham, and ED Thomas. "What radiation dose for DLA-identical canine marrow grafts? [published erratum appears in Blood 1989 Feb;73(2):624]." Blood 72, no. 4 (October 1, 1988): 1300–1304. http://dx.doi.org/10.1182/blood.v72.4.1300.bloodjournal7241300.
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In view of reported attempts at marrow grafting after nuclear accidents with a broad range of radiation exposures, the present study explored the total-body irradiation (TBI) conditions needed for engraftment in a canine model by using marrow from DLA-identical littermates. Previous studies have shown that such grafts are consistently successful when recipients are exposed to 920 cGy of TBI delivered at a rate of 7 cGy/min from opposing dual cobalt sources. The present TBI doses were all in the lethal range. Five dogs were administered 450 cGy; seven dogs, 600 cGy; five dogs, 700 cGy; and five dogs, 800 cGy of TBI administered at 7 cGy/min. They received a median of 3.3 x 10(8) marrow cells/kg intravenously after completion of radiation. Results showed transient allogeneic marrow engraftment in all dogs administered the lowest dose of TBI studied (450 cGy). Importantly, transient grafts permitted four of five dogs to live long enough for autologous marrow recovery to occur. At increasing radiation doses, 600, 700, and 800 cGy, the risk of graft failure lessened, with 3 of 7, 2 of 5, and 1 of 5 dogs, respectively, showing graft rejection. Fewer dogs survived with autologous marrow recovery, and more showed sustained allogeneic engraftment (4 of 7, 3 of 5, and 4 of 5 dogs, respectively). We conclude that DLA-identical littermate marrow grafts are beneficial in the setting of otherwise lethal radiation exposures, with most dogs either experiencing sustained allogeneic engraftment or surviving with autologous marrow recovery due to the extended support provided by a transient allogeneic graft.
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Mahan, KT. "Calcaneal donor bone grafts." Journal of the American Podiatric Medical Association 84, no. 1 (January 1, 1994): 1–9. http://dx.doi.org/10.7547/87507315-84-1-1.
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Autogenous bone grafting is an important part of many foot and ankle surgical procedures. Although alternative bone graft materials such as allogeneic bone are available, autogenous bone continues to be the material of choice for many procedures. The calcaneus provides a source of small amounts of autogenous corticocancellous or cancellous bone. The author describes the surgical technique for procurement of calcaneal bone grafts. Twenty-five cases are reviewed. The morbidity associated with procuring calcaneal bone grafts is favorably compared with that associated with procuring bone from other donor sites.
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Wu, Douglas, and Kathryn Wood. "An analysis of the adaptive immune response towards an embryonic stem cell grafts." Clinical & Investigative Medicine 30, no. 4 (August 1, 2007): 98. http://dx.doi.org/10.25011/cim.v30i4.2879.
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Background: Although clinical transplantation has had enormous impact on the treatment of premature organ failure, shortage of donor organs continues to be a crucial limiting factor. Embryonic stem cells represent an attractive potential source of replacement tissue because of their inherent pluripotentiality and ability to self-renew. However, before any ES cell-based cellular replacement strategies can be considered, many issues must be addressed. Among these is an evaluation of the potential immune response elicited by any ES cell graft. Because ES cells express very low levels of MHC class I and no MHC class II, their immunogenicity has been questioned. Here we utilize a BM3 TCR transgenic model to analyze the adaptive immune response against an ES cell graft in vivo.
Methods: BM3 CD8 TCR-tg T cells (H2K background) specific for the MHC class I molecule H2Kb were labelled with CFSE and adoptively transferred into CBA rag recipients. The following day, ES cells derived from a CBA, B6, or CBK background were implanted beneath the kidney capsule of adoptively transferred mice. Response of the CD8 T cells was measured via CSFE division profiling and graft infiltration.
Results: CFSE division profile of naïve BM3 CD8 T cells was unaltered by the presence of either a syngeneic or an allogeneic ES cell graft. These naïve cells were also unable to recognize and infiltrate either a syngeneic or allogeneic ES cell graft on days 5 and 10 post-implantation, despite strong expression of the MHC class I molecule H2Kb by engrafted allogeneic ES cells. On the other hand, H2Kb+ islets begun to be infiltrated by day 5, and were obliterated by a vigorous allogeneic response by day 10. When H2Kb+ islets were implanted into the same kidney as allogeneic ES cells (opposite poles), islet grafts were rapidly infiltrated by CD4 and CD8 T cells and destroyed, but ES cell grafts exhibited markedly reduced cellular infiltrate. In contrast to naïve BM3 CD8 T cells, however, activated cells recognized and mounted an aggressive cytotoxic response against an allogeneic ES cell graft which could be detected by day 6 and resulted in complete graft destruction by day 10.
Conclusions: Under certain circumstances, an ES cell graft may have reduced immunogenicity as compared with other conventional tissue or solid organ allografts. This may be due to their lack of passenger APC, which may in turn cripple their ability to elicit a robust allogeneic response via the direct pathway of allorecognition. However, because of their strong upregulation of allogeneic MHC class I molecules after transplantation, they are still likely to elicit a significant rejection response when transplanted into recipients replete with both CD4 and CD8 T cells.
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Katagiri, Hiroki, Hideyuki Koga, and Takeshi Muneta. "Review of Shino et al (1984) on anterior cruciate ligament reconstruction using allograft in the dog." Journal of ISAKOS: Joint Disorders & Orthopaedic Sports Medicine 3, no. 3 (December 7, 2017): 186–92. http://dx.doi.org/10.1136/jisakos-2017-000131.
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This article discusses the original1984 publication of ‘Replacement of the anterior cruciate ligament using an allogeneic tendon graft. An experimental study in the dog’. The original classic study discovered the revascularisation and remodelling of an allograft for anterior cruciate ligament reconstruction (ACLR) using microangiographic, histological and biomechanical methods. The original classic study suggested that a transplanted allogeneic tendon can substitute for an autograft in ACLR. The original classic study suggested this new option to the orthopaedic medical community. Currently, an allograft is one of the main alternatives used for ACLR. This article begins with a detailed summary of the original classic study. Second, this article reviews the historical perspectives, the scientific and societal effect and the effect of the original classic study on present practices. Finally, the ultimate goal of this article is to validate the use of allogeneic tendon grafts in ACLR with the current evidence of clinical studies and animal experiments and to elucidate any remaining questions regarding allogeneic tendon grafts, which could then be resolved through studies in the near future.
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Schwarz, N., G. Schlag, M. Thurnher, J. Eschberger, HP Dinges, and H. Redl. "Fresh autogeneic, frozen allogeneic, and decalcified allogeneic bone grafts in dogs." Journal of Bone and Joint Surgery. British volume 73-B, no. 5 (September 1991): 787–90. http://dx.doi.org/10.1302/0301-620x.73b5.1894667.
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Felix, Nathan J., W. June Brickey, Robert Griffiths, Jinghua Zhang, Luc Van Kaer, Thomas Coffman, and Jenny P. Y. Ting. "H2-DMα−/− Mice Show the Importance of Major Histocompatibility Complex–Bound Peptide in Cardiac Allograft Rejection." Journal of Experimental Medicine 192, no. 1 (June 26, 2000): 31–40. http://dx.doi.org/10.1084/jem.192.1.31.
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The role played by antigenic peptides bound to major histocompatibility complex (MHC) molecules is evaluated with H2-DMα−/− mice. These mice have predominantly class II–associated invariant chain peptide (CLIP)-, not antigenic peptide–bound, MHC class II. H2-DMα−/− donor heart grafts survived three times longer than wild-type grafts and slightly longer than I-Aβb−/− grafts. Proliferative T cell response was absent, and cytolytic response was reduced against the H2-DMα−/− grafts in vivo. Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection. Removal of both H2-DMα and β2-microglobulin (β2m) in cardiac grafts lead to greater (8–10 times) graft survival, whereas removal of β2m alone did not have any effect. These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.
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Swanger, Sharon A., Birgit Neuhuber, B. Timothy Himes, Ajay Bakshi, and Itzhak Fischer. "Analysis of Allogeneic and Syngeneic Bone Marrow Stromal Cell Graft Survival in the Spinal Cord." Cell Transplantation 14, no. 10 (November 2005): 775–86. http://dx.doi.org/10.3727/000000005783982594.
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Bone marrow stromal cells (MSC) are attractive candidates for developing cell therapies for central nervous system (CNS) disorders. They can be easily obtained, expanded in culture, and promote modest functional recovery following transplantation into animal models of injured or degenerative CNS. While syngeneic MSC grafts can be used efficiently, achieving long-term survival of allogeneic MSC grafts has been a challenge. We hypothesize that improved graft survival will enhance the functional recovery promoted by MSC. To improve MSC graft survival, we tested two dosages of the immune suppressant cyclosporin A (CsA) in an allogeneic model. Syngeneic transplantation of MSC where cells survive well without immune suppression was used as a control. Sprague-Dawley rats treated with standard dose (n = 12) or high-dose (n = 12) CsA served as allogeneic hosts; Fisher 344 rats (n = 12) served as syngeneic hosts. MSC were derived from transgenic Fisher 344 rats expressing human placental alkaline phosphatase and were grafted into cervical spinal cord. Animals treated with standard dose CsA showed significant decreases in allograft size 4 weeks posttransplantation; high CsA doses yielded significantly better graft survival 4 and 8 weeks posttransplantation compared to standard CsA. As expected, syngeneic MSC transplants showed good graft survival after 4 and 8 weeks. To investigate MSC graft elimination, we analyzed immune cell infiltration and cell death. Macrophage infiltration was high after 1 week in all groups. After 4 weeks, high-dose CsA and syngeneic animals showed significant reductions in macrophages at the graft site. Few T lymphocytes were detected in any group at each time point. Cell death occurred throughout the study; however, little apoptotic activity was detected. Histochemical analysis revealed no evidence of neural differentiation. These results indicate that allogeneic transplantation with appropriate immune suppression permits long-term survival of MSC; thus, both allogeneic and syngeneic strategies could be utilized in devising novel therapies for CNS injury.
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Wang, Zejing, Mohamed L. Sorror, Wendy Leisenring, Gary Schoch, David G. Malonely, Brenda M. Sandmaier, and Rainer F. Storb. "Transfusion Requirements in Allogeneic Hematopoietic Cell Transplantation (HCT) Recipients Given Either Myeloablative or Nonmyeloablative Conditioning, and Effect of ABO Incompatibility on HCT Outcomes." Blood 112, no. 11 (November 16, 2008): 3268. http://dx.doi.org/10.1182/blood.v112.11.3268.3268.
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Abstract We retrospectively assessed 1) overall platelet (PLT) and red blood cell (RBC) transfusion requirements within the first 100 days after allogeneic among HCT recipients given either nonmyeloablative (n=365) or myeloablative conditioning (n=1430); 2) transfusion requirements among nonmyeloablative recipients given grafts from related (n=187) vs. unrelated donors (n=178), and grafts from ABO matched (n=203) vs. ABO mismatched donors (n=159); and 3) the impact of ABO incompatibility on HCT outcomes among nonmyeloablative recipients. Table 1 summarizes results. We confirmed that myeloablative recipients were more likely to receive both PLT and RBC transfusions than nonmyeloablative recipients (both p<0.0001). Subsequent analyses were restricted to nonmyeloablative recipients. Both PLT and RBC transfusion requirements were increased among recipients of unrelated grafts (both p<0.0001) and those with major or bi-directional ABO mismatched grafts (p = 0.019 and p=0.003, respectively). No statistically significant differences were observed in cumulative incidences of graft rejection/failure, grades II-IV acute GVHD and in 3-year survivals between ABO-matched, minor-mismatched, and major/bidirectional mismatched pts (p=0.89, 0.48, and 0.49, respectively). Times to disappearance of anti-donor IgM and IgG isohemagglutinins were not statistically significantly different among major or bi-directional ABO mismatched related (43 days for both) vs. unrelated recipients (58 and 57 days, p=0.20 and 0.27, respectively). Major/bidirectional ABO-mismatched recipients with grades II-IV vs. 0–I acute GVHD had comparable likelihoods of reaching IgM (p=0.20) and IgG (p=0.63) titer endpoints. In conclusion, nonmyeloablative pts had reduced PLT and RBC transfusion requirements compared to myeloablative pts. Among nonmyeloablative pts, unrelated (vs. related) grafts and ABO-incompatibility (vs. ABO compatibility) between donors and recipients led to increased PLT and RBC transfusion requirements. ABO incompatibility did not increase graft rejection nor GVHD or adversely affect survival after non-myeloablative HCT. The tempo of disappearance of anti-donor isohemagglutinin titers was not influenced by donor type or occurrence of GVHD. Table 1. Percentage of patients requiring at least one PLT or RBC transfusion. % of Patients Requiring Transfusions N PLT p-value† RBC p-value† † p-value from Chi-square test. * Reference group for comparisons. £ Information were missing from 3 patients. Non-myeloablative 365 36% * 76% * Myeloablative 1430 99% <0.0001 96% <0.0001 Non-myeloablative Related grafts 187 25% * 67% * Unrelated grafts 178 47% <0.0001 86% <0.0001 Non-myeloablative£ ABO-matched 203 33% * 70% * ABO minor mismatched 79 33% 0.95 80% 0.11 Major bi-directional ABO-mismatched 80 48% 0.019 88% 0.003 Non-myeloablative ABO-mismatched Related grafts 66 32% * 77% * Unrelated grafts 93 46% 0.068 88% 0.067
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Waller, Edmund K., Brent R. Logan, Wayne A. C. Harris, Steven M. Devine, David L. Porter, Shin Mineishi, John M. McCarty, et al. "Improved Survival After Transplantation of More Donor Plasmacytoid Dendritic or Naïve T Cells From Unrelated-Donor Marrow Grafts: Results From BMTCTN 0201." Journal of Clinical Oncology 32, no. 22 (August 1, 2014): 2365–72. http://dx.doi.org/10.1200/jco.2013.54.4577.
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Purpose To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor–mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. Patients and Methods Fresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). Results Patients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of > median number of pDCs, naïve CD8+ T cells (CD8Tns), or naïve CD4+ T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P = .025; CD8Tns, 56% v 37%; P = .012; CD4Tns, 55% v 37%; P = .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. Conclusion Donor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation.
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Weinberg, Kenneth, Bruce R. Blazar, John E. Wagner, Edward Agura, Brenna J. Hill, Monika Smogorzewska, Richard A. Koup, Michael R. Betts, Robert H. Collins, and Daniel C. Douek. "Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation." Blood 97, no. 5 (March 1, 2001): 1458–66. http://dx.doi.org/10.1182/blood.v97.5.1458.
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Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA+ naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4+ and CD8+ cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.
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Gergis, Usama, Naima Ali Al-Mulla, Segovia Javier, Rania Hafez, Adrienne A. Phillips, Sebastian Mayer, Tsiporah B. Shore, et al. "Hematopoietic Recovery after in-Vivo T-Cell Depleted Allogeneic Stem Cell Transplant- Effects of ABO Incompatibility, Rhesus Incompatibility and Acute Gvhd." Blood 128, no. 22 (December 2, 2016): 5745. http://dx.doi.org/10.1182/blood.v128.22.5745.5745.
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Abstract Background: Transfusion needs after allogeneic transplantation are closely associated with morbidity, cost of transplantation and may also be associated with long-term outcome. In an effort to better predict determinants of recovery after reduced intensity conditioning, we analyzed 214 consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT) at our institution from January 2012 to December 2013. Patients and Methods: We excluded patients who experienced early (in the first 4 months) relapse (n=28), non-relapse mortality (n=28) or who experienced prolonged hospital stay before day 100 for transplant related complications (n=51). One hundred and seven patients had uneventful recovery until day 100 and met the inclusion criteria. The majority of patients received Fludarabine and melphalan conditioning (87%). Approximately one third each of the patients had HLA-identical related, HLA-matched unrelated donors or underwent haplo-cord transplantation. Recipients of HLA-identical related or unrelated donor transplant received alemtuzumab and post-transplant tacrolimus. Haplo-cord recipients received thymoglobulin and post-transplant tacrolimus and mycophenolate. Patients and transplant characteristics are summarized in table 1. T-tests were used for comparison between groups. Results: In our analysis of 107 patients who underwent T cell depleted allogeneic transplantation and fared well at day 100, the determinants of prolonged anemia were ABO incompatibility (p=0.006), rhesus incompatibility (p=0.01) and acute graft versus host disease (aGVHD) (p=0.02). Whereas prolonged thrombocytopenia was only associated with the development of any grade aGVHD (p=0.04). At day 100, the hematopoietic recovery of haplo-cord grafts is similar to matched related and unrelated grafts. Conclusion: ABO incompatibility, rhesus incompatibility and occurrence of acute graft vs host disease are the major determinants of red blood cell recovery. Occurrence of acute graft vs host disease is a major determinant of platelet recovery. Of interest, the use of umbilical cord blood grafts combined with haplo-identical grafts is associated with recovery of red blood cells and platelets that is similar to that of adult donor grafts. Disclosures No relevant conflicts of interest to declare.
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Hsu, Jack W., Nosha Farhadfar, Hemant S. Murthy, Brent Logan, Stephanie Bo-Subait, Noelle V. Frey, Steven C. Goldstein, et al. "Impact of Cryopreservation of Donor Grafts on Outcomes of Allogeneic Hematopoietic Cell Transplant (HCT)." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-136778.
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Introduction: Cryopreservation of peripheral blood stem cell (PBSC) or bone marrow (BM) grafts is rarely performed, thus information about the effect of cryopreservation on graft characteristics and HCT outcomes is limited. Given the global pandemic leading to changing practices for donor graft collection and increasing utilization of cryopreservation, we evaluated the outcomes of HCT recipients who received either fresh or cryopreserved allogeneic BM or PBSC grafts. The primary endpoint was engraftment. Secondary endpoints were incidence of acute graft-vs.-host disease (aGVHD), relapse, transplant related mortality (TRM), disease free survival (DFS), and overall survival (OS). Methods: We included 7397 patients transplanted between 2013 and 2018. 1883 cryopreserved graft recipients were divided into three cohorts based on graft source and donor type: matched related (MRD) PBSC (n=1,051), matched unrelated (MUD) PBSC (n=678), and matched related or unrelated bone marrow donors (n=154). All patients received conventional calcineurin-based GVHD prophylaxis strategies. Patients who received cryopreserved grafts were matched with 5514 patients who received fresh adjusting for graft type (BM vs. PB), donor source (MRD vs. 8/8 MUD), Disease Risk Index (DRI, low risk vs. intermediate risk vs. high risk), recipient age (within 5-years) and propensity score (within 1 standard deviation from pooled sample). The propensity score was based on age, Karnofsky score, diagnosis, disease risk index, HCT-comorbidity index, and conditioning intensity. The level of statistical significance for the main analyses was p<0.01 due to multiple comparisons. The reason for cryopreservation was available on a subset of URD product recipients. Results: Baseline characteristics for all cohorts are shown in Table 1. CD34+ doses reflect enumeration at infusion. In univariate analyses, rates of graft failure and neutrophil recovery at day 28 were similar for cryopreserved and fresh grafts for BM or related PBSC recipients but differed in cryopreserved vs. fresh MUD PBSC (5% vs 2%, p<0.001 and 87 vs 94%, p<0.001, respectively). Rates of platelet recovery within 28 days were similar in marrow cohorts, but lower with cryopreserved related (92% vs 96%, p<0.001) and MUD PBSC (87 vs 94%, p<0.001) grafts. In matched pair multivariable analyses, there were no significant differences in any outcomes with cryopreserved vs fresh BM grafts, irrespective of donor type. With related donor PBSC, cryopreservation was associated with decreased platelet recovery (HR=0.73, CI=0.68-0.78, p<0.001) and an increased risk of both grade II-IV (HR=1.27, CI=1.09-1.48, p=0.002) and grade III-IV (HR=1.48, CI=1.19-1.84, p<0.001) aGVHD, but had no impact on other outcomes. In contrast, with MUD PBSC grafts, cryopreservation was associated with delayed engraftment of neutrophils (HR=0.77, CI=0.71-0.84, p<0.001) and platelets (HR=0.61, CI=0.56-0.66, p<0.001), an increased risk of TRM (HR=1.4, CI=1.18-1.66, p<0.001) and relapse (HR=1.32, CI=1.11-1.58, p=0.002), and decreased DFS (HR=1.36, CI=1.20-1.55, p<0.001) and OS (HR=1.38, CI=1.22-1.58, p<0.001) but did not affect the incidence of aGVHD. In a subset analysis of 299 URD recipients, the most common reason for cryopreservation was delays due to patient-related events, eg., additional chemotherapy, infection. These recipients had decreased OS compared to products cryopreserved for non-patient reasons (HR=0.65, CI=0.44-0.96, p=0.029). Conclusions: The retrospective nature of this analysis, and the fact that cryopreservation is likely to have been performed in recipients with a different (higher) risk profile compared to those receiving fresh products limits our ability to draw firm confusions. Despite these limitations, we conclude that cryopreservation in some patient populations may have a negative impact on engraftment and transplant outcomes. The decision to cryopreserve donor grafts, particularly PBSC grafts, should be carefully considered and highlights the need for further investigation of the effect of cryopreservation of allogeneic grafts where patient factors can be controlled for. Disclosures Farhadfar: CSL Behring: Research Funding; Incyte pharmaceutical: Other: Member of GVHD advisory forum. Frey:Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria. Devine:Magenta Therapeutics: Consultancy. Shaw:Orca Bio: Consultancy. Wingard:Shire: Other: Personal Fees - serve on data monitoring committee for clinical trial; Ansun: Other: Personal Fees - serve on data monitoring committee for clinical trial; Merck: Other: Personal Fees - serve on data monitoring committee for clinical trial; Cidara: Other: Personal Fees - serve on data monitoring committee for clinical trial; ReViral: Other: Personal Fees - serve on data monitoring committee for clinical trial.
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Reshef, Ran, Austin P. Huffman, Amy Gao, Marlise R. Luskin, Noelle V. Frey, Saar I. Gill, Elizabeth O. Hexner, et al. "High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning." Journal of Clinical Oncology 33, no. 21 (July 20, 2015): 2392–98. http://dx.doi.org/10.1200/jco.2014.60.1203.
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Purpose To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. Patients and Methods We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content. Results Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 108 CD8 cells per kilogram optimally segregated patients receiving CD8hi and CD8lo grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8hi graft, whereas approximately half of younger donors provided CD8hi grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8lo doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8hi doses (P = .03), but not for recipients of younger unrelated donor CD8lo grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors. Conclusion Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT.
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Cho, Christina, and Miguel-Angel Perales. "Expanding Therapeutic Opportunities for Hematopoietic Stem Cell Transplantation: T Cell Depletion as a Model for the Targeted Allograft." Annual Review of Medicine 70, no. 1 (January 27, 2019): 381–93. http://dx.doi.org/10.1146/annurev-med-120617-041210.
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Allogeneic hematopoietic cell transplantation is a fundamental part of the treatment of hematologic malignancies and marrow failure syndromes, but complications including graft-versus-host disease, prolonged immune deficiency and infection, and organ toxicities, as well as relapse, remain obstacles to improved overall survival. As the cellular characteristics of the allograft can exert significant impact on outcomes, the development of more strategically designed grafts represents a rich area for therapeutic intervention. We describe the use of ex vivo T cell–depleted grafts as a model for the targeted graft and review evolving knowledge and approaches for further refinement of allografts to improve patient outcomes.
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Li, Jian-Ming, Ying Wang, Katarzyna Darlak, Lauren T. Southerland, Mohammad S. Hossain, Cynthia R. Giver, James A. Waschek, and Edmund K. Waller. "Blocking Vasoactive Intestinal Peptide Signaling Enhances Anti-Viral Immunity without Increased Graft Versus Host Disease in Murine Allogeneic Bone Marrow Transplantation." Blood 118, no. 21 (November 18, 2011): 1002. http://dx.doi.org/10.1182/blood.v118.21.1002.1002.
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Abstract Abstract 1002 Background: Vasoactive intestinal peptide (VIP) is a neuropeptide hormone and type 2 cytokine that inhibits Th1 immunity and induces the generation of regulatory T-cells. We have recently reported that non-transplanted mice “knocked-out” for VIP and syngeneic transplant recipients of VIP-knockout (KO) BM had dramatically improved survival, viral clearance, and increased numbers of specific antiviral CD8+ T-cells following murine cytomegalovirus (mCMV) infection (JI 2011. 187:1057–65). In this study, we used a small molecule VIP antagonist as well as VIP-KO mice to further investigate effects and mechanisms of VIP-signaling on antiviral immune responses in wild type (WT) non-transplanted mice and following allogeneic BMT. Methods: B10BR (CD45.2, H-2Kk) and CB6/J F1 (CD45.2, H-2Kb/d) mice were transplanted with 3 × 103 FACS-sorted hematopoietic stem cells (HSC), 5 × 104 dendritic cells (DC), and 0.3, 1, or 3 × 106 splenic T-cells either from VIP-KO (CD45.2, H-2Kb) or WT donors after myeloablative conditioning (11Gy). WT mice and BMT recipients transplanted with WT grafts were treated with daily subcutaneous injection of VIP antagonist (10 μg/100μL per mouse) or PBS for 7 days (from one day prior to infection to 6 days post-infection). BALB/C mice, B6 VIP-KO and WT littermates, as well as CB6/J F1 BMT recipients, were infected with graded doses (LD10, LD50 and LD90) of mCMV by intraperitoneal injection. Survival, viral load, antigen specific T-cells, and clinical scores of graft versus host disease (GvHD) were assessed at distinct time-points post-BMT or after mCMV infection. The expression of co-stimulatory or co-inhibitory markers (CD25, CD62L, CD69, PD-1, FoxP3, PD-L1, CD80, CD86, and MHC-II) and intracellular expression of cytokines (IL-10, IFN-γ, TNF-α, and IL-12) on T-cells and DC from the mice were measured by flow cytometry. Results: Improved survival was seen in mCMV-infected allogeneic B6→CB6/J F1 transplant recipients of VIP-KO grafts (100%) compared with recipients of WT grafts treated with PBS (40%). Allogeneic recipients of VIP-KO grafts and allogeneic recipients of WT grafts treated with VIP antagonist had increased viral clearance and enhanced in vivo killing of viral-peptide-pulsed targets compared with PBS-treated recipients of WT grafts. No difference in the incidence or severity of acute GvHD was seen in allogeneic BMT recipients of graded doses of VIP-KO versus WT splenic T-cells (0.3, 1, and 3 × 106) in murine MHC mis-matched BMT models. Allogeneic transplant recipients of VIP-KO grafts and WT grafts treated with VIP antagonist, infected with low dose mCMV, had lower levels of PD-L1 and PD-1 expression on DC and T-cells, respectively, and higher levels of CD80, CD86 and MHC-II expression on conventional DC (cDC) and plasmacytoid DC (pDC) compared with recipients of WT allografts treated with PBS. Recipients of VIP-KO grafts and recipients treated with VIP antagonist had higher-levels of IL-12+ cDC, activated CD25+/CD69+ CD4 and CD8 T-cells, and more mCMV-M45-peptide MHC-I tetramer+ CD8+ T-cells compared with recipients of WT grafts treated with PBS. Absence of VIP-signaling led to enhanced intracellular expression of IFN-γ and less IL-10 expression in T-cells from mCMV-infected recipients of VIP-KO B6→CB6/J F1 allogeneic transplants, and mCMV-infected, VIP antagonist-treated recipients of WT allogeneic transplants. In the absence of mCMV infection, the numbers of regulatory T cells (Treg) were similar among VIP-KO mice, WT mice treated with VIP antagonist, and PBS-treated WT controls. In contrast, mCMV-infected VIP-KO mice had significantly fewer Treg compared with mCMV- infected WT mice, non-infected WT mice and non-infected VIP-KO mice. Conclusion: Genetic or pharmacological blockade of VIP-signaling enhanced both innate and adaptive antiviral immune responses in allogeneic BMT recipients without significantly elevating GvHD. Selective targeting of VIP-signaling represents a novel therapeutic approach to enhance antiviral immunity in the setting of immunodeficiency and allogeneic BMT. Disclosures: No relevant conflicts of interest to declare.
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Bolton, E. M., J. A. Gracie, J. D. Briggs, J. Kampinga, and J. A. Bradley. "Cellular requirements for renal allograft rejection in the athymic nude rat." Journal of Experimental Medicine 169, no. 6 (June 1, 1989): 1931–46. http://dx.doi.org/10.1084/jem.169.6.1931.
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This study has examined the ability of adoptively transferred CD4+ and CD8+ T cells to mediate rejection of a fully allogeneic DA renal graft in the PVG nude rat. Transfer, at the time of transplantation, of naive CD4+ T cells caused rapid graft rejection and primed CD4+ cells were several times more potent. In contrast, naive or specifically sensitized CD8+ cells were entirely ineffective at mediating renal allograft rejection. Whereas nonrejecting grafts showed only a mild cellular infiltrate, rejecting grafts in CD4+ reconstituted animals showed a substantial infiltrate and many of the infiltrating cells had a phenotype (MRC OX8+, MRC OX19-), consistent with NK cells. Experiments using a mAb (HIS 41) against an allotypic determinant of the leukocyte common antigen confirmed that the majority (greater than 80%) of the cellular infiltrate in rejecting grafts derived from the host rather than from the CD4+ inoculum. Infiltrating mononuclear cells, obtained from rejecting allografts 7 d after transplantation in CD4+-injected PVG nude hosts, showed high levels of in vitro cytotoxicity against not only kidney donor strain Con A blasts but also third-party allogeneic Con A blasts, as well as against both NK and LAK susceptible targets. When splenocytes from nontransplanted nude PVG rats were tested in vitro they also demonstrated high levels of lytic activity against both NK and LAK susceptible targets as well as allogeneic Con A blasts, which were not susceptible to lysis by spleen cells from euthymic rats. These findings suggest that injected CD4+ cells may cause renal allograft rejection by the recruitment of extrathymically derived, widely alloreactive cells into the kidney in this model of graft rejection.
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Prokopchuk-Gauk, Oksana, Joanna McCarthy, Peter Duggan, Meer-Taher Shabani-Rad, and Nicole L. Prokopishyn. "Impact of ABO Incompatibility on Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 3394. http://dx.doi.org/10.1182/blood.v128.22.3394.3394.
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Abstract Introduction: The selection of an allogeneic hematopoietic stem cell transplant (allo-HSCT) donor is highly dependent on human leukocyte antigen (HLA) allele profile matching with that of the intended recipient to minimize graft-related complications and improve post-transplant outcomes. Although ABO compatibility simplifies recipient transfusion needs, transplantation of an ABO incompatible graft has been identified not to have a significant impact on marrow engraftment or recipient survival. We completed an audit of adult allo-HSCT recipients of the Alberta Bone Marrow and Blood Cell Transplant Program to evaluate the impact of ABO incompatibility on engraftment in our allo-HSCT recipient population. Methods: A retrospective review including all adult allo-HSCT recipients between January 1, 2008 and January 1, 2015 was performed. Data was obtained from review of cellular therapy laboratory electronic records, with blood group confirmation by the transfusion medicine laboratory information system. Statistical calculations were completed using the unpaired t test. Results:A total of 513 adult patients underwent 528 allo-HSCT procedures (493 peripheral blood, 12 marrow, 23 cord blood). The mean HSCT recipient age was 46 (range 17-66) with 291 (57%) male recipients. The most common HSCT indication was acute myeloid leukemia. All allo-HSCT recipients received myeloablative conditioning. A total of 91% of recipients were conditioned with a regimen of Fludarabine-Busulfan-ATG, with or without total body irradiation. ABO compatibility status for allo-HSCT procedures included the following: 264 (50%) ABO identical grafts, 125 (24%) grafts with a minor incompatibility, 113 (21%) grafts with a major incompatibility, and 26 (5%) grafts with bidirectional incompatibility. HLA matching data was available for 447 allo-HSCT procedures. A total of 350 (78%) patients were recipients of fully HLA matched grafts (340 peripheral blood, 9 marrow, 1 cord blood). Taking into consideration ABO compatibility status, 10/10 HLA matched peripheral blood or marrow grafts were provided to 89% of ABO identical graft recipients, 77% of recipients each with a minor or major incompatibility, and 65% of recipients with a bidirectional incompatibility. Cellular engraftment including the number of days until absolute neutrophil count (ANC) > 1.0 x 106/L and platelet count > 20 x 109/L was available for 496 (94%) of all transplant procedures. A total of 34 transplant recipients did not successfully engraft one or both cell lines. A summary of recipient engraftment data for each category of ABO matching according to stem cell source appears in Table 1. Conclusion:In our study population, the risk of non-engraftment is lowest in recipients of ABO identical peripheral blood or marrow source donor stem cells. Time to cellular engraftment following allo-HSCT transplant with peripheral blood or marrow source stem cells of minor or major ABO incompatibility is similar to that of an ABO identical donor, while platelet engraftment appears to be prolonged in the setting of a bidirectional incompatibility. However, the small number of recipients of grafts with a bidirectional incompatibility and the large standard deviation affects our confidence in this result. The impact of ABO matching on engraftment appears to be the greatest in cord blood transplants. The risk of cellular non-engraftment is variable among all ABO compatibility categories, though the time to platelet engraftment is significantly prolonged in recipients of grafts with major ABO or bidirectional incompatibility. These findings are limited by our small cord blood recipient population and the presence of some degree of HLA mismatching in nearly all recipients of cord blood transplants evaluated. Further study is required in larger populations of cord blood transplant recipients to better understand the impact of ABO compatibility status on marrow engraftment, together with variables including the cellular composition of the cord blood graft and host immune factors. Table 1 Rate of non-engraftment and days to neutrophil and platelet engraftment following allo-HSCT according to ABO compatibility, including standard deviation and statistical calculation (*indicates statistically significant value). Table 1. Rate of non-engraftment and days to neutrophil and platelet engraftment following allo-HSCT according to ABO compatibility, including standard deviation and statistical calculation (*indicates statistically significant value). Disclosures No relevant conflicts of interest to declare.
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Arellano, Martha L., Susan G. Moore, Ragini Kudchadkar, Christopher R. Flowers, Amelia A. Langston, Sagar Lonial, Mary J. Lechowicz, and Edmund K. Waller. "Predictors of More Rapid Lymphoid Reconstitution after Allogeneic Transplantation." Blood 104, no. 11 (November 16, 2004): 3159. http://dx.doi.org/10.1182/blood.v104.11.3159.3159.
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Abstract Introduction: Aberrant post-transplant immune reconstitution contributes to the major risks of graft versus host disease (GVHD), infection, and relapse following allogeneic hematopoietic progenitor cell transplantation. Faster lymphocyte engraftment has been found to predict better clinical outcomes in patients after autologous and allogeneic bone marrow transplantation. The purpose of our study was to investigate factors that may contribute to more rapid lymphocyte engraftment in patients who underwent transplantation using grafts procured from HLA-matched volunteer unrelated donors. Methods:We analyzed 47 recipients of BM (n=13) and G-CSF mobilized blood hematopoietic progenitor cell grafts (n=34) for post-transplant lymphoid reconstitution, and constituents of the graft that predicted early lymphoid recovery. Diagnoses included 28 patients with AML/MDS/MPD, 6 with lymphoma/CLL, 6 with ALL, 3 with CML, 2 with MM and 2 with AA, with a median age of 43 years (range 17–68). 34 patients received TBI or busulfan-based myeloablative regimens; 13 patients received fludarabine and low-dose TBI. Numbers of T-cell, NK, B-cell, and dendritic cell subsets in the grafts were enumerated by flow cytometry. Our primary end point was lymphocyte engraftment at day+30 (ALC > 500 x 2 days). Secondary analyses included: univariate and multivariate models exploring the relationship between graft constituents and early lymphoid recovery. Results: With a median follow-up of 1 year (range 1–32 months), 11 (23%) patients died prior to lymphocyte engraftment; 2 patients failed to achieve ALC > 500; and 20 (43%) patients were alive with stable lymphocyte engraftment. The median dose of CD34+ cells administered was 5.35 x 10E6 cells/kg; and the median dose of CD3+ cells was 211 x 10E6 cells/kg.The mean absolute lymphocyte count (ALC) on day +30 for the entire group was 714 ± 125 cells per mcL, with a median time to achieve an ALC > 500/mcL for 2 consecutive days of 23 days (range 0–111 days). In univariate analyses, higher doses of the following T-cell subsets in the graft were predictive of faster lymphocyte engraftment (all x 10E6 cells/kg): CD3+ > 296 (p=0.01), CD4+ > 172 (p=0.04), CD123+11c- (DC2) > 3.38 (p=0.03), and gamma-delta T- cells > 5.50 (p=0.01). The graft content of CD34+ cells and other graft constituents were not significantly associated with faster lymphoid engraftment. Stepwise multivariate Cox regression models including all graft constituents, conditioning regimen and patient characteristics determined that gamma-delta T-cell dose in the graft was the only factor associated with faster lymphocyte engraftment (p < 0.01). Faster lymphocyte engraftment was not significantly associated with CMV reactivation, or the incidence of either acute or chronic GVHD. Conclusions: The kinetics of lymhoid reconstitution following allogeneic volunteer unrelated donor transplantation are associated with the content of donor T-cells and DC2 in the graft. Faster lymphoid reconstitution was not associated with less CMV infection nor improved survival in this relatively small population. Ongoing studies are examining the role of lymphoid reconstitution in post-transplant outcomes in a larger data base of allogeneic transplant recipients.
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Alho, Antti, Erkki O. Karaharju, Olli Korkala, Erkki M. Laasonen, Teddy Holmström, and Carl Müller. "Allogeneic grafts for bone tumor: 21 cases of osteoarticular and segmental grafts." Acta Orthopaedica Scandinavica 60, no. 2 (January 1989): 143–53. http://dx.doi.org/10.3109/17453678909149242.
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Mickevicius, Tomas, Alius Pockevicius, Audrius Kucinskas, Rimtautas Gudas, Justinas Maciulaitis, and Arvydas Usas. "Nondestructive Assessment of Articular Cartilage Electromechanical Properties after Osteochondral Autologous and Allogeneic Transplantation in a Goat Model." CARTILAGE 11, no. 3 (July 12, 2018): 348–57. http://dx.doi.org/10.1177/1947603518786543.
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Objective To determine the applicability of a minimally invasive diagnostic device to evaluate the quality of articular cartilage following autologous (OAT) and allogeneic (OCA) osteochondral graft transplantation in goat model. Design OAT grafts were harvested from lateral femoral condyles (LFCs) and transplanted into osteochondral defects created in medial femoral condyles (MFCs) of contralateral knees. OCA grafts were transplanted into MFC condyles after in vitro storage. Autologous platelet-rich plasma (PRP) was administered intraarticularly after the surgery and at 1 and 2 months postoperatively. OAT and OCA grafts were evaluated macroscopically (Oswestry arthroscopy score [OAS]), electromechanically (quantitative parameter, QP), and histologically (O’Driscoll score, safranin O staining intensity) at 3 and 6 months after transplantation. Results were compared with preoperative graft evaluation. Results Transplanted cartilage deteriorated within 6 months in all groups. Cartilage quality was better retained in OAT group compared with a decline in OCA group. QP and OAS scores were comparable in OAT and OCA groups at 3 months, but superior in OAT group at 6 months, according to all the methods applied. PRP injections significantly improved QP and OAS score at 6 months compared with 3 months in OAT group. QP moderately correlated with OAS, O’Driscoll score, and safranin O staining intensity. Conclusions Grafts did not retain preoperative quality parameters at 6 months follow-up; however, OAT were superior to OCA grafts. PRP may have a beneficial effect on macroscopic and electromechanical properties of cartilage; however, histological improvement is yet to be proved. Electromechanical diagnostic device enables reliable assessment of transplanted cartilage.
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Schroeder, Mark A., Michael P. Rettig, Sandra Lopez, Stephanie Christ, Mark Fiala, William Eades, Fazia A. Mir, et al. "Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft." Blood 129, no. 19 (May 11, 2017): 2680–92. http://dx.doi.org/10.1182/blood-2016-09-739722.
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Key Points Plerixafor is a safe, effective, rapid mobilizing agent when administered intravenously. Lower rates of GVHD and CMV viremia with plerixafor-mobilized grafts may be related to a unique cellular composition of the graft.
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Barbosa, Isabel L., Patricia A. Benevides, Claudia C. Sousa, Sergio B. Machado Lopes, Ana R. Tavares, Fernando Campilho, Antonio Campos, et al. "Cellular Composition of Allogeneic and Autologous PBPC Grafts and Patient Engraftment." Blood 106, no. 11 (November 16, 2005): 5277. http://dx.doi.org/10.1182/blood.v106.11.5277.5277.
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Abstract We studied the influence of graft populations on the hematological recovery of PBPC transplants. The data shown is a retrospective study of 36 patients (median age 41, range 16–67) who underwent allogeneic transplant from HLA-matched siblings and 29 patients (median age 25, range 20–68) who underwent autologous PBPC transplants between June 2002 and July 2005. The cell populations studied were: total nucleated cells (TNC), CD34+ cells, T cells (CD3+) and NK cells (CD3−/CD56+). The hematological engraftment was evaluated by the following parameters: time to absolute neutrophil count (ANC)>0.5x109/L, platelets>20x109/L, absolute lymphocyte count (ALC)>0.5x109/L and ALC at day +15. The median cell doses infused in patients are summarised in Table 1 Table 1- PBPC cell population infused per Kg of patient body weight TNC x 108 CD34+ cells x 106 T cells x 108 NK cells x 106 *median **range Allogeneic 12.8 * 7.5 3.2 36.8 3.6 – 30.7 ** 3.4 – 10.5 0.7 – 9.8 4.2 – 136.6 Autologous 12 3.26 3.5 29 4.1– 51.0 2.2 – 7.0 0.1– 0.4 7.4 – 351 Spearman correlation analysis showed for the allogeneic PBPC grafts, correlation between TNC and NK cells collected (p=0.002), whereas for the autologous grafts there was correlation between TNC and NK cells (p=0.000) and CD34+ cells (p=0.004) collected. To asses the importance of cell dose infused in the hematologic engraftment of the two patient groups, neutrophil, platelet and lymphocyte recovery was determined (Table 2). Table 2- Patient engraftment Day to ANC>0.5x109/L Day to platelets>0.2x109/L Day to ALC>0.5x109/L ALC day +15 cell/μl *median **range Allogeneic 11 * 12 11 715 8 – 15 ** 8 – 29 2 – 14 190 – 4670 Autologous 11 11 12 1178 7 – 13 8 – 18 10 – 21 230 – 4410 For both groups of patients, engraftment occurred within the expected time and ALC day +15 cell/μl was different (median 715 cell/μl and 1178 cell/μl for allogeneic and autotransplanted patients respectively). For the allogeneic transplanted patients, Spearman correlation analysis showed that the dose of NK cells infused was significantly correlated with ALC at day +15 (p=0.021). There was also correlation between the time to platelets and ANC engraftment (p=0.008) and time to platelets engraftment and ALC at day +15 (p=0.046). For the autologous patients there was no correlation between cell populations of the grafts and the hematologic engraftment. Our data provide evidence that in allogeneic transplants the NK dose influences early ALC recovery. However, it is important to continue this study to balance the importance of cell population doses both in allogeneic and autologous transplants.
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Shegarfi, Hamid, and Olav Reikeras. "Review Article: Bone Transplantation and Immune Response." Journal of Orthopaedic Surgery 17, no. 2 (August 2009): 206–11. http://dx.doi.org/10.1177/230949900901700218.
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Bone is the second most common transplant tissue after blood, with the iliac crest autologous graft being most used. Bone transplantation induces osteogenesis to repair bone defects. Despite being the most efficient, autogenous bone requires an additional incision and its supply may be inadequate. Deep-frozen allogeneic bone can be an alternative, but is at risk of microbiological contamination, transmission of unrecognised germs, delayed incorporation, and cellular and humoral immune reactions. Synthetic graft substitutes combine scaffolding properties with biological elements to stimulate cell proliferation and differentiation and eventually osteogenesis. However, they generally lack osteoinductive or osteogenic properties and have various effects on bone healing. We present an overview of bone grafts and graft substitutes in clinical use, and the immune responses to allogeneic bone.
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Lee, Seok-Joo, Hyun-Je Kim, Na-ri Byun, and Chung-Gyu Park. "Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment." Cell Transplantation 29 (January 1, 2020): 096368972091387. http://dx.doi.org/10.1177/0963689720913876.
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Anti-CD154 blockade-based regimens remain unequaled in prolonging graft survival in various organ transplantation models. Several studies have focused on transplantation tolerance with the anti-CD154 blockade, but none of these studies has investigated the mechanisms associated with its use as the sole treatment in animal models, delaying our understanding of anti-CD154 blockade-mediated immune tolerance. The purpose of this study was to investigate the mechanism underlying the anti-CD154 monoclonal antibody (mAb) blockade in inducing immune tolerance using an intrahepatic murine allogeneic islet transplantation model. Allogeneic BALB/c AnHsd (BALB/c) islets were infused into the liver of diabetic C57BL/6 (B6) mice via the cecal vein. Anti-CD154 mAb (MR1) was administered on −1, 0, 1, 3, 5, and 7 d posttransplantation at 0.5 mg per mouse. We showed that short-term MR1 monotherapy could prolong the allogeneic islet grafts to more than 250 d in the murine intrahepatic islet transplantation model. The second islet grafts transplanted under the kidney capsule of the recipients were protected from rejection. We also found that rejection of same-donor skin grafts transplanted to the tolerant mice was modestly delayed. Using a DEREG mouse model, FoxP3+ regulatory T (Treg) cells were shown to play important roles in transplantation tolerance. In mixed lymphocyte reactions, Treg cells from the tolerant mice showed more potency in suppressing BALB/c splenocyte-stimulated Teff cell proliferation than those from naïve mice. In this study, we demonstrated for the first time that a short-term anti-CD154 mAb single treatment could induce FoxP3+ Treg cell-mediated immune tolerance in the intrahepatic murine allogeneic islet transplantation model.
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Bar, BM, GW Santos, and AD Donnenberg. "Reconstitution of antibody response after allogeneic bone marrow transplantation: effect of lymphocyte depletion by counterflow centrifugal elutriation on the expression of hemagglutinins." Blood 76, no. 7 (October 1, 1990): 1410–18. http://dx.doi.org/10.1182/blood.v76.7.1410.1410.
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Abstract The generation of ABO hemagglutinins was used as a model to assess the tempo of reconstitution of antibody responses in recipients of elutriated (CCE) and nonelutriated (nonCCE) HLA matched bone marrow allografts. The study included 29 CCE recipients (10 major, 6 minor, and 1 major/minor ABO-mismatched, and 12 ABO-matched) and 40 nonCCE recipients (14 major, 12 minor, 2 major/minor, and 12 matched). Plasma volume in the graft and in blood product transfusions was uncorrelated with changes in hemagglutinin titers and therefore was excluded as a significant source of antibody. Removal of graft lymphocytes by CCE did not result in prolongation of host-derived hemagglutinins in recipients of major ABO-mismatched grafts. However, CCE resulted in a complete abrogation of the adoptive transfer of donor-derived antibody as detected in recipients of minor ABO-mismatched grafts. Despite the absence of adoptively transferred donor immunity in recipients of CCE grafts, they had hemagglutinin levels comparable with those of recipients of nonCCE grafts by 6 months after transplantation. This demonstrates that recipients of elutriated marrow were competent to mount de novo responses at that time. The strong correlation between donor pretransplant hemagglutinin titer and recipient titer 1 year after bone marrow transplantation in recipients of nonCCE grafts suggests that even late after transplant, antibody remains the product of adoptively transferred memory cells in recipients of grafts containing large numbers of mature lymphocytes.
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Bar, BM, GW Santos, and AD Donnenberg. "Reconstitution of antibody response after allogeneic bone marrow transplantation: effect of lymphocyte depletion by counterflow centrifugal elutriation on the expression of hemagglutinins." Blood 76, no. 7 (October 1, 1990): 1410–18. http://dx.doi.org/10.1182/blood.v76.7.1410.bloodjournal7671410.
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The generation of ABO hemagglutinins was used as a model to assess the tempo of reconstitution of antibody responses in recipients of elutriated (CCE) and nonelutriated (nonCCE) HLA matched bone marrow allografts. The study included 29 CCE recipients (10 major, 6 minor, and 1 major/minor ABO-mismatched, and 12 ABO-matched) and 40 nonCCE recipients (14 major, 12 minor, 2 major/minor, and 12 matched). Plasma volume in the graft and in blood product transfusions was uncorrelated with changes in hemagglutinin titers and therefore was excluded as a significant source of antibody. Removal of graft lymphocytes by CCE did not result in prolongation of host-derived hemagglutinins in recipients of major ABO-mismatched grafts. However, CCE resulted in a complete abrogation of the adoptive transfer of donor-derived antibody as detected in recipients of minor ABO-mismatched grafts. Despite the absence of adoptively transferred donor immunity in recipients of CCE grafts, they had hemagglutinin levels comparable with those of recipients of nonCCE grafts by 6 months after transplantation. This demonstrates that recipients of elutriated marrow were competent to mount de novo responses at that time. The strong correlation between donor pretransplant hemagglutinin titer and recipient titer 1 year after bone marrow transplantation in recipients of nonCCE grafts suggests that even late after transplant, antibody remains the product of adoptively transferred memory cells in recipients of grafts containing large numbers of mature lymphocytes.
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Benichou, Gilles, Yohei Yamada, Seok-Hyun Yun, Charles Lin, Michael Fray, and Georges Tocco. "Immune recognition and rejection of allogeneic skin grafts." Immunotherapy 3, no. 6 (June 2011): 757–70. http://dx.doi.org/10.2217/imt.11.2.
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Faille, A., D. Maraninchi, E. Gluckman, A. Devergie, N. Balitrand, F. Ketels, and C. Dresch. "Granulocyte Progenitor Compartments after Allogeneic Bone Marrow Grafts." Scandinavian Journal of Haematology 26, no. 3 (April 24, 2009): 202–14. http://dx.doi.org/10.1111/j.1600-0609.1981.tb01648.x.
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Pileggi, Antonello, R. Damaris Molano, Thierry Berney, Hirohito Ichii, Sergio San Jose, Elsie Zahr, Raffaella Poggioli, Elina Linetsky, Camillo Ricordi, and Luca Inverardi. "Prolonged Allogeneic Islet Graft Survival by Protoporphyrins." Cell Transplantation 14, no. 2-3 (February 2005): 85–96. http://dx.doi.org/10.3727/000000005783983160.
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Transplantation of islets of Langerhans in patients with type 1 diabetes allows for improved metabolic control and insulin independence. The need for chronic immunosuppression limits this procedure to selected patients with brittle diabetes. Definition of therapeutic strategies allowing permanent engraftment without the need for chronic immunosuppression could overcome such limitations. We tested the effect of the use of protoporphyrins (CoPP and FePP), powerful inducers of the cytoprotective protein hemeoxygenase 1 (HO-1), on allogeneic islet graft survival. Chemically induced diabetic C57BL/6 mice received DBA/2 islets. Treatment consisted in peritransplant administration of CoPP or saline. Islets were either cultured in the presence of FePP or vehicle before implant. Short-course administration of CoPP led to long-term islet allograft survival in a sizable proportion of recipients. Long-term graft-bearing animals rejected third-party islets while accepting a second set donor-specific graft permanently, without additional treatment. Preconditioning of islets with FePP by itself led to improved graft survival in untreated recipients, and provided additional advantage in CoPP-treated recipients, resulting in an increased proportion of long-term surviving grafts. Preconditioning of the graft with protoporphyrins prior to implant resulted in reduction of class II expression. Administration of protoporphyrins to the recipients of allogeneic islets also resulted in transient powerful immunosuppression with reduced lymphocyte proliferative responses, increased proportion of regulatory cells (CD4+CD25+), decreased mononuclear cell infiltrating the graft, paralleled by a systemic upregulation of HO-1 expression. All these mechanisms may have contributed to the induction of donor-specific hyporesponsiveness in a proportion of the protoporphyrintreated animals.
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Ildstad, S. T., S. M. Wren, J. A. Bluestone, S. A. Barbieri, and D. H. Sachs. "Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance." Journal of Experimental Medicine 162, no. 1 (July 1, 1985): 231–44. http://dx.doi.org/10.1084/jem.162.1.231.
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Mixed allogeneically reconstituted mice (B10 + B10.D2----B10) that specifically accept B10.D2 tail skin allografts were examined for in vivo and in vitro immunocompetence, patterns of hematopoietic repopulation, and in vitro reactivity. In vitro, mixed allogeneic chimeras (B10 + B10.D2----B10) manifested specific tolerance in mixed lymphocyte reactions and cell-mediated lympholysis to B10 and B10.D2 splenocytes, with normal responses to third-party (B10.BR) cells. Such chimeras were immunocompetent in B cell and helper T cell responses, as assessed by their primary plaque forming cell responses to in vivo sheep red blood cell immunization. This is in contrast to fully allogeneic chimeras, which responded less well. In addition, survival of the mixed allogeneic chimeras in a conventional animal facility was superior to that of fully allogeneic chimeras, and similar to syngeneically reconstituted (B10----B10) mice. Specific tolerance to skin grafts, degree of allogeneic engraftment, and persistence of chimerism was also assessed in a noncongenic mixed allogeneic combination (B10 + C3H----B10). Such animals manifested specific hyporeactivity to C3H skin allografts, but eventual chronic rejection of the grafts occurred in spite of stable and persistent mixed chimerism. MHC-congenic (B10.BR) skin grafts were accepted indefinitely in the same animals, suggesting that skin-specific non-major histocompatibility complex antigens were responsible for rejection of the C3H skin allografts.
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Pierini, Antonio, Bettina Iliopoulou, Heshan Peiris, Magdiel Perez Cruz, Jeanette Baker, Katie Hsu, William Strober, et al. "The Use of Monoclonal Antibody Directed Chimeric Antigen Receptors to Facilitate Conventional T Cell and Treg Control of GvHD and Tissue Tolerance in Murine Models." Blood 128, no. 22 (December 2, 2016): 3355. http://dx.doi.org/10.1182/blood.v128.22.3355.3355.
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Abstract INTRODUCTION Regulatory T cells (Treg) modulate allograft immune responses and Treg-based cellular therapies can be used for prevention of graft-versus-host disease (GvHD) following hematopoietic cell transplantation and for prevention of allograft rejection following tissue or organ transplantation. Treg adoptive transfer has limitations including that Treg do not necessarily home to sites where they are needed and can become inactivated in inflammatory milieus. METHODS We used new technologies of T cell engineering to force the expression of a chimeric antigen receptor on T cells and Treg that recognizes labeled therapeutic monoclonal antibodies (mabCAR), allowing for precise control of their localization in vivo. The mabCAR recognizes fluorescein isothiocyanate (FITC) through a FITC-specific single-chain variable fragment fused to a CD28 and TCRζ costimulatory domain. Any monoclonal antibody (mab) coupled to FITC within its Fc domain can be recognized. We tested this approach with T cells and Treg to ameliorate GvHD and induce tolerance to pancreatic islet grafts. RESULTS We first tested our mabCAR construct in conventional T cells (Tcon) which when transfected and stimulated with a FITC-mab become activated and expressed higher levels of CD44 (p=0.0003), CD25 (p=0.009) and produced more IFNγ (p=0.04). To test if mabCAR transient transfection alters Tcon homing after adoptive transfer, we injected luc+ mabCAR Tcon directed against MAdCAM1 (a gut and lymph node endothelial integrin) or SDF1 (a chemokine mainly expressed in the bone marrow) into allogeneic hosts. MAdCAM1-directed Tcon mainly homed to the gut and lymph nodes, while SDF1-directed Tcon homed to bones and spleen. SDF1-directed Tcon induced a milder GvHD (p<0.001), demonstrating that cell homing impacts GvHD severity. We then tested mabCAR Treg ability to maintain their suppressive activity in vitro and in vivo. We found that mabCAR transiently transfected into Treg have increased ability to proliferate in response to anti-CD3/CD28 stimulatory beads (p<0.01) and highly suppress Tcon proliferation when co-cultured with allogeneic irradiated splenocytes. We injected MAdCAM1 directed Treg in an allogeneic GvHD model and these mabCAR Treg prolonged survival (p=0.03), improved GvHD score (p<0.001) and mouse weight profile (p<0.001), thus demonstrating that mabCAR Treg retain regulatory functions. Finally, we tested if mabCAR Treg could induce tolerance to allogeneic pancreatic islet grafts in sublethally irradiated hosts. Luc+gfp+ mabCAR Treg homed and expanded over time (p<0.05) to the site of the allogeneic islet grafts (right kidney capsule) when FITC-anti-allogeneic MHC-I mab directed the Treg as compared to isotype mab controls (see figure). Allo-MHC-I directed mabCAR-Treg prolonged allogeneic islet graft survival in comparison to isotype-mabCAR Treg (p=0.002) allowing for production of higher insulin levels. To assess if allo-MHC-I Treg promoted antigen-specific tolerance, we performed secondary skin graft transplantation. We found that mice which received MHC-I Treg showed a significant delay in the rejection of skin grafts from mice with the same MHC mismatch as the previous islet-allografts in comparison to third-party skin grafts (p=0.02) offering strong evidence that CAR-Treg could be used to enhance antigen-specific graft protection. CONCLUSION MabCAR expression can be used to control immune cell homing after transfer in different models according to localizing mab availability. We believe that the mabCAR approach may represent a new tool for optimizing cellular therapies to modulate GvHD and for inducing tolerance in islet and organ transplantation. Figure Figure. Disclosures Pierini: Stanford University: Patents & Royalties. Iliopoulou:Stanford University: Patents & Royalties. Negrin:Stanford University: Patents & Royalties. Kim:Stanford University: Patents & Royalties. Meyer:Stanford University: Patents & Royalties.
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Lee, R. S., M. J. Grusby, L. H. Glimcher, H. J. Winn, and H. Auchincloss. "Indirect recognition by helper cells can induce donor-specific cytotoxic T lymphocytes in vivo." Journal of Experimental Medicine 179, no. 3 (March 1, 1994): 865–72. http://dx.doi.org/10.1084/jem.179.3.865.
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In vitro studies have revealed that help for cytotoxic T lymphocyte (CTL) induction can be mediated through several pathways, including direct recognition of allogenic class II antigens by CD4+ cells, direct recognition of allogeneic class I antigens by "CD4-independent" CD8+ cells, and "indirect" recognition of peptides of alloantigens presented in association with self class II molecules. Whereas good evidence for the two direct pathways is available in vivo, there is relatively little evidence to show that indirect recognition can initiate graft rejection. This study examined the role of indirect allorecognition during the generation of CTLs in mice as they rejected major histocompatibility complex (MHC) class II-deficient skin after depletion of CD8+ T cells in vivo. Recipients were depleted of CD8+ T cells by in vivo treatment with anti-CD8 monoclonal antibody and then grafted with allogeneic skin lacking MHC class II antigens. The mice rejected the skin grafts rapidly. Although flow cytometry showed marked depletion of CD8+ T cells in these mice, we found that (a) CD8+ CTLs were generated and sensitized to MHC class I antigens of the donor; (b) the generation of the CD8+ CTLs required the help in vivo of CD4+ cells, as well as priming with the allogeneic skin graft; and (c) the CD4+ T helper cells were sensitized indirectly to donor peptides presented in association with class II antigens on recipient antigen-presenting cells. These results provide evidence that indirect recognition can provide effective help for CTL induction during graft rejection, even when the cytotoxic T cells are sensitized by determinants expressed only on the donor graft.
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Lima, Julio Leonardo de Oliveira, Daniel Isaac Sendyk, Wilson Roberto Sendyk, Cristiane Ibanhes Polo, Luciana Correa, and Maria Cristina Zindel Deboni. "Growth Dynamic of Allogeneic and Autogenous Bone Grafts in a Vertical Model." Brazilian Dental Journal 29, no. 4 (August 2018): 325–34. http://dx.doi.org/10.1590/0103-6440201801994.
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Abstract Several techniques have been proposed for vertical bone regeneration, and many of them use bone autogenous and allogeneic grafts. The purpose of this study was to compare demineralised freeze-dried bone allografts (DFDBA), fresh-frozen (FF) allografts, autogenous bone grafts to find differences between volumetric and histological quantity of bone formation and vertical bone growth dynamic. A vertical tissue regeneration bone model was performed in rabbit calvarias under general anaesthesia. Four hollow cylinders of pure titanium were screwed onto external cortical bone calvarias in eight rabbits. Each one of the cylinders was randomly filled with one intervention: DFDBA, FF, autogenous bone, or left to be filled with blood clot (BC) as control. Allogeneic grafts were obtained from a ninth animal following international standardised protocols for the harvesting, processing, and cryopreservation of allografts. Autogenous graft was obtained from the host femur scraping before adapting hollow cylinders. Animals were euthanized at 13 weeks. Vertical volume was calculated after probe device measurements of the new formed tissue inside the cylinders and after titanium cylinders were removed. Histomorphometry and fluorochrome staining were used to analyse quantity and dynamic of bone formation, respectively. Results showed that DFDBA and fresh-frozen bone improved the velocity and the quantity of bone deposition in distant portions of the basal plane of grafting. Remaining material in allograft groups was more intense than in autogenous group. Both allografts can be indicated as reliable alternatives for volume gain and vertical bone augmentation.