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van Agteren, Madelon, Willem Weimar, Annelies E. de Weerd, Peter A. W. te Boekhorst, Jan N. M. Ijzermans, Jaqueline van de Wetering, and Michiel G. H. Betjes. "The First Fifty ABO Blood Group Incompatible Kidney Transplantations: The Rotterdam Experience." Journal of Transplantation 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/913902.
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This study describes the single center experience and long-term results of ABOi kidney transplantation using a pretransplantation protocol involving immunoadsorption combined with rituximab, intravenous immunoglobulins, and triple immune suppression. Fifty patients received an ABOi kidney transplant in the period from 2006 to 2012 with a follow-up of at least one year. Eleven antibody mediated rejections were noted of which 5 were mixed antibody and cellular mediated rejections. Nine cellular mediated rejections were recorded. Two grafts were lost due to rejection in the first year. One-year graft survival of the ABOi grafts was comparable to 100 matched ABO compatible renal grafts, 96% versus 99%. At 5-year follow-up, the graft survival was 90% in the ABOi versus 97% in the control group. Posttransplantation immunoadsorption was not an essential part of the protocol and no association was found between antibody titers and subsequent graft rejection. Steroids could be withdrawn safely 3 months after transplantation. Adverse events specifically related to the ABOi protocol were not observed. The currently used ABOi protocol shows good short and midterm results despite a high rate of antibody mediated rejections in the first years after the start of the program.
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Petra, Hřibová, Honsová Eva, Brabcová Irena, Hrubá Petra, and Viklický Ondřej. "Molecular Profiling of Acute and Chronic Rejections of Renal Allografts." Clinical and Developmental Immunology 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/509259.
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Both antibody mediated (AMR) and T-cell mediated (TCMR) rejections either acute or chronic represent the main reason for late graft dysfunction. In this study we aimed to evaluate differences in the intrarenal expression patterns of immune system related genes in acute and chronic rejections. Graft biopsies were performed and evaluated according to Banff classification. Using the TaqMan Low Density Array, the intrarenal expressions of 376 genes relating to immune response (B-cell activation, T-cell activation, chemokines, growth factors, immune regulators, and apoptosis) were analyzed in the four rejection categories: chronic AMR, chronic TCMR, acute AMR, and acute TCMR. The set of genes significantly upregulated in acute TCMR as compared to acute AMR was identified, while no difference in gene expressions between chronic rejections groups was found. In comparison with functioning grafts, grafts that failed within the next 24 months after the chronic rejection morphological confirmation presented at biopsy already established severe graft injury (low eGFR, higher proteinuria), longer followup, higher expression of CDC20, CXCL6, DIABLO, GABRP, KIAA0101, ME2, MMP7, NFATC4, and TGFB3 mRNA, and lower expression of CCL19 and TRADD mRNA. In conclusion, both Banff 2007 chronic rejection categories did not differ in intrarenal expression of 376 selected genes associated with immune response.
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Suhorukovs, Vadims, and Tatjana Tihomirova. "Impact of Subclinical Acute Rejection on Renal Graft Function: Results of Three-Year Follow-Up." Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences 67, no. 1 (April 1, 2013): 42–46. http://dx.doi.org/10.2478/prolas-2013-0008.
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Notwithstanding that in the last years the immediate results of kidney transplantation have been improved, there has been no adequate improvement of long-term results. Therefore, more attention is being paid to the so-called subclinical rejections of renal grafts, detected by protocol biopsies, as a possible factor affecting renal function in late period. The aim of this study was to determine the frequency of subclinical rejections and their impact on further renal graft function. Within the frame of the study 40 protocol biopsies were performed in 26 patients with immediate and stable renal graft function. In 17 (65.4%) of them a subclinical rejection of IA-IIA degree was detected. In nine patients with subclinical rejection, treatment with steroids was applied, while eight recipients did not receive any additional therapy. In follow-up, in a period of three years there was no statistically significant difference in blood creatinine level, glomerular filtration rate, number of clinical rejections during the monitoring period, and three-year survival of the transplanted kidney in patients, regardless of where the treatment of subclinical rejection was applied. The results of our study did not indicate any impact of subclinical rejection on renal graft function in the late post-operation period.
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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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Dennert, G., C. G. Anderson, and J. Warner. "T killer cells play a role in allogeneic bone marrow graft rejection but not in hybrid resistance." Journal of Immunology 135, no. 6 (December 1, 1985): 3729–34. http://dx.doi.org/10.4049/jimmunol.135.6.3729.
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Abstract Results of recent experiments have provided compelling evidence supporting the hypothesis that the acute rejection of bone marrow transplants by allogeneic and semiallogeneic recipients is principally due to the action of natural killer (NK) cells. The observed specificity of graft rejection is likely induced by target-specific antibody that guides the NK cells in an antibody-dependent cytolytic reaction resulting in the elimination of the graft. The sole involvement of NK cells in marrow graft rejection, however, is contradicted by several observations that point to the environment of specific T cells. Results presented in this paper demonstrate that in allogeneic marrow graft rejection models, T killer cells are capable of causing graft rejection provided a prior sensitization phase is allowed. Thus, mice not able to reject marrow grafts in a primary response via their NK cells will do so in a primed secondary response via their T cells. Rejection is specific in that only marrow grafts H-2 identical to the sensitizing marrow graft are rejected. Sensitization for NK cell independent marrow graft rejection can be accomplished by prior priming with allogeneic tumor cells or by injection of cloned T killer cells. In contrast to bone marrow allograft rejection, the hybrid resistance model in which F1 hybrid mice reject parental marrow grafts does not appear to induce T killer cells in vivo. Neither marrow grafts nor tumor cells prime F1 hybrids for a second-set parental graft rejection. Moreover, F1 hybrid antiparental T killer cells induced in vitro and adoptively transferred in vivo fail to transfer hybrid resistance. Therefore, there appear to be potent mechanisms acting in vivo that suppress the action or induction of F1 hybrid T killer cells specific to parental antigens.
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Tullo, A. B. "Graft rejection." Eye 12, no. 4 (July 1998): 609–10. http://dx.doi.org/10.1038/eye.1998.152.
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Allocco, Jennifer Brianne, Christine McIntosh, Peter Wang, Michelle McKeague, Ying Wang, Alexandra Cassano, Stephen Z. Xie, et al. "Variegated levels of alloreactive T cell dysfunction in transplantation tolerance determine graft vulnerability to infection-triggered rejection." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 173.08. http://dx.doi.org/10.4049/jimmunol.210.supp.173.08.
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Abstract While advances have been made in therapies that achieve tolerance in mouse models of transplantation, successful tolerance remains vulnerable to inflammatory insults, which can trigger graft rejection. To identify strategies for improving the robustness of tolerance, we aim to better understand the mechanisms by which grafts are rejected after donor-specific tolerance is established. In a mouse model of cardiac allograft tolerance in which late infection with Listeria monocytogenes (Lm) can trigger graft rejection, we previously showed that host CD4 +T cells reactive to host MHC-II presenting a donor MHC-I-derived peptide (TCR75 cells) became intrinsically dysfunctional if the alloantigen persisted for 3 weeks or greater. Intriguingly, infection-dependent transplant rejection was not associated with transcriptional or functional reinvigoration of these cells. We hypothesized that there might be heterogeneity in the level of dysfunction of alloreactive T cells depending on duration of their cognate alloantigen persistence. Unlike TCR75 cells, CD4 +T cells specific for host MHC-II presenting a peptide derived from donor MHC Class II (TEa cells), a graft antigen that declines post-transplantation, retained functionality during tolerance induction. Consequently, TEa but not TCR75 cells expanded following Lm-infection, supporting a role for TEa-like cells in driving infection-triggered rejection. Prolonging T cell exposure to cognate alloantigens aggravated TEa dysfunction and rendered grafts resistant to Lm-dependent rejection. These findings demonstrate that inducing dysfunction in a broader array of allospecific T cells, by prolonging exposure to more alloantigens, lessens graft vulnerability to infections. Supported by the UChicago Growth Development and Disabilities Training Program (T32 HD007009). AHA predoctoral fellowships (20PRE35210946, 3PRE14550022 and 15PRE22180007). NIH T32-AI007090. UChicago Cardiovascular Pathophysiology and Biochemistry Training Grant (T32 HL07237). HHMI Med-into-Grad Program training grant (56006772). NIAID Grant P01AI-97113.
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Onyema, Oscar Okwudiri, Yizhan Guo, Qing Wang, Andrew E. Gelman, Daniel Kreisel, Elizabeth A. Jacobsen, and Alexander Sasha Krupnick. "Eosinophils alleviate lung allograft rejection through their modulation of CD8+ T Cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 55.14. http://dx.doi.org/10.4049/jimmunol.200.supp.55.14.
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Abstract Introduction Based on the accumulation of eosinophils (eos) in rejected lung grafts, it was widely held that eos perpetuate lung graft rejection. However, we showed recently in a mechanistic study that eos mediate lung graft tolerance. As eos are also present in rejected lungs, we therefore explore the possibility of a different role of eos in lung graft rejection. Method Using orthotopic left lung transplantation of MHC-1 mismatched Balb/c (H2Kd) donors to C57BL/6J (H2Kb) recipients, with or without co-stimulatory blockade immunosuppression, we quantified the number of eos in lung grafts at day 7 post-transplant (D7). Th1, Th2 and Th17 cytokine profiles of D4 lung grafts were analyzed by quantitative PCR. D7 eos were also analyzed for their expression of Th1, Th2 and Th17 signature genes. The role of eos was examined in iPHIL mice that experience selective ablation of eos after Diphtheria toxin (DT) administration. Balb/c left lungs transplanted into DT or vehicle treated iPHIL mice without immunosuppression were analyzed histologically and flow cytometrically at D4. Results We observed similar numbers of eos, higher Th1 polarization, lower IL33, a Th2 cytokine and less Th17 polarization of the lung microenvironment, and higher expression of the Th1 signature genes among eos, in rejecting compared to accepting lung grafts. Eos deficiency was associated with more rapid lung graft rejection, evidenced in higher CD8+ T cell proliferation, lower CD4/CD8 ratio, and enhanced T cell differentiation to effector memory phenotype. Conclusion Our results indicate that eos directly ameliorate lung graft rejection even in the absence of immunosuppression. This calls for a revalidation of the importance of eos in lung allograft pathology.
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Hall, B. M. "Mechanisms maintaining enhancement of allografts. I. Demonstration of a specific suppressor cell." Journal of Experimental Medicine 161, no. 1 (January 1, 1985): 123–33. http://dx.doi.org/10.1084/jem.161.1.123.
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DA rats treated with hyperimmune anti-PVG serum and grafted with (DA X PVG)F1 heart grafts in which graft survival was prolonged for greater than 75 d were used to examine the cellular mechanisms that maintain the state of specific unresponsiveness found in these animals. The capacity of lymphocytes from these animals to effect or inhibit graft rejection on adoptive transfer to irradiated heart-grafted hosts was tested. Spleen cell populations and the T cell subpopulation separated from spleen cells in vitro failed to restore rejection of PVG heart grafts in irradiated DA recipients but restored third party Lew graft rejection. Whole spleen cells had the capacity to suppress the ability of normal DA LNC to cause graft rejection, but T cells from spleen only delayed the restoration of rejection. LNC and recirculating T cells from rats with enhanced grafts adoptively restored PVG rejection, however. These studies show that the state of specific unresponsiveness that follows the induction of passive enhancement is dependent in part upon active suppression, which is induced or mediated by T lymphocytes. The recirculating pool of lymphocytes in these animals is not depleted of specific alloreactive cells with the capacity to initiate and effect rejection. Thus, these animals' unresponsiveness is not like that found in transplantation tolerance induced in neonatal rats, but is, in part, due to a suppressor response that can inhibit normal alloreactive cells' capacity to initiate and effect rejection.
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Priftakis, P., G. Bogdanovic, G. Tyden, and T. Dalianis. "Polyomaviruria in Renal Transplant Patients Is Not Correlated to the Cold Ischemia Period or to Rejection Episodes." Journal of Clinical Microbiology 38, no. 1 (January 2000): 406–7. http://dx.doi.org/10.1128/jcm.38.1.406-407.2000.
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ABSTRACT Polyomaviruria was observed in one-third of all renal transplant patients, irrespective of whether their renal grafts came from a living or cadaver donor, and was not correlated to graft rejection episodes. This suggests that the renal graft ischemia period is not the major cause of polyomavirus reactivation and that reactivation of polyomavirus is not a dominant cause of graft rejection.
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Pinna, A., M. Salvo, S. Dore, and F. Carta. "Corneal Graft Rejection after Penetrating Keratoplasty for Keratoconus in Turner's Syndrome." European Journal of Ophthalmology 15, no. 2 (March 2005): 271–73. http://dx.doi.org/10.1177/112067210501500216.
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Purpose To report a patient with Turner's syndrome who developed graft rejection after penetrating keratoplasty (PK) for keratoconus and to review the ophthalmic literature on the association between keratoconus and Turner's syndrome. Methods A woman with bilateral keratoconus and Turner's syndrome (45,XO) was referred for progressive visual loss in the right eye. Best-corrected visual acuity was 20/400 in the right eye. Slit-lamp examination revealed corneal thinning with ectatic protrusion of the central cornea and Vogt's striae in the right eye. The patient underwent PK in the right eye in January 2001. She developed graft rejection in April 2003 and visual acuity dropped to hand motion. After treatment with topical and systemic steroids and systemic cyclosporine A, visual acuity recovered to 20/80 in July 2003. Results The authors know of only three other reported patients (six eyes) with keratoconus in Turner's syndrome. Five eyes underwent PK with good visual rehabilitation, but one developed immunologic graft rejection 7 years after surgery. On the whole, considering the current report and the other cases described in the literature, graft rejection occurred in 2 out of 6 eyes (33.3%). The graft survival rate was 80% after 2 years and 40% after 7 years. Conclusions The results suggest that grafts for keratoconus in patients with Turner's syndrome might have an increased risk of immunologic rejection. Corneal grafts in Turner's syndrome need to be monitored closely. Early detection of graft rejection and aggressive treatment with topical and systemic steroids and systemic cyclosporine A can save the graft and restore useful vision.
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Ilano, A. L., M. V. McConnell, K. E. Gurley, A. Spinelli, N. W. Pearce, and B. M. Hall. "Cellular basis of allograft rejection in vivo. V. Examination of the mechanisms responsible for the differing efficacy of monoclonal antibody to CD4+ T cell subsets in low- and high-responder rat strains." Journal of Immunology 143, no. 9 (November 1, 1989): 2828–36. http://dx.doi.org/10.4049/jimmunol.143.9.2828.
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Abstract MRC OX35, an anti-CD4 mAb, was used to treat high responder Wistar Furth (W/F) (RT1u) and low responder DA (RT1a) rats which had been grafted with directly vascularized hearts from PVG (RT1c) rats across a full MHC plus non-MHC incompatibility. Four doses of mAb at 7 mg/kg given in the first 2 wk postgrafting induced indefinite graft survival (greater than 150 days) in DA hosts, but only delayed rejection to 18 to 42 days in W/F as compared to rejection times of 6 to 8 days in untreated rats. The extension of MRC OX35 treatment to 6 wk in W/F rats induced indefinite graft survival in three of six rats. During treatment MRC OX35 therapy only partially depleted CD4+ cells, and all circulating CD4+ cells were coated with MRC OX35. The capacity of naive CD4+ and CD8+ cells from W/F and DA to be activated to PVG alloantigen was compared both in vitro in an MLC assay and in vivo by an adoptive transfer assay of their capacity to restore rejection of PVG heart grafts in irradiated syngeneic hosts. CD4+ cells from both W/F and DA proliferated in MLC and restored graft rejection. W/F CD8+ cells both proliferated in MLC and restored rejection, but DA CD8+ cells neither proliferated nor reconstituted rejection. Examination of lymphocytes from MRC OX35 treated hosts with long-surviving grafts showed that they were neither depleted of CD4+ T cells nor did they lack the capacity to proliferate to PVG Ag in MLC, this response being similar to that to third-party Ag or by naive lymphocytes. Compared to first-set rejection, PVG skin graft rejection was delayed 2 to 3 days in W/F and 10 to 12 days in DA rats with long-surviving grafts after MRC OX35 therapy, whereas they rejected third-party skin grafts in first-set tempo. These studies show that differences in graft survival in anti-CD4 treated low and high responder strains may be due to the inherent capacity of CD8+ cells to be activated to effect rejection independent of CD4+ cells in W/F but not in DA. In those hosts that accept grafts, there is no evidence of clonal deletion, but there appears to be a form of unresponsiveness akin to that induced in adult rats by other immunosuppressive therapies that protects the graft from rejection.
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Lam, Helene, and M. Reza Dana. "Corneal Graft Rejection." International Ophthalmology Clinics 49, no. 1 (2009): 31–41. http://dx.doi.org/10.1097/iio.0b013e3181924e23.
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Panda, Anita, M. Vanathi, A. Kumar, Yeshoda Dash, and Satya Priya. "Corneal Graft Rejection." Survey of Ophthalmology 52, no. 4 (July 2007): 375–96. http://dx.doi.org/10.1016/j.survophthal.2007.04.008.
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Fuller, Barbara F. "Organ Graft Rejection." AORN Journal 41, no. 4 (April 1985): 738–45. http://dx.doi.org/10.1016/s0001-2092(07)66297-8.
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Azuma, Haruhito, and Nicholas L. Tilney. "Chronic graft rejection." Current Opinion in Immunology 6, no. 5 (January 1994): 770–76. http://dx.doi.org/10.1016/0952-7915(94)90083-3.
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Dennert, G., C. G. Anderson, and J. Warner. "Induction of bone marrow allograft rejection and hybrid resistance in nonresponder recipients by antibody: is there evidence for a dual receptor interaction in acute marrow graft rejection?" Journal of Immunology 136, no. 11 (June 1, 1986): 3981–86. http://dx.doi.org/10.4049/jimmunol.136.11.3981.
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Abstract Acute marrow graft rejection in allogeneic or semiallogeneic donor-recipient mouse combinations has been suggested to be caused by natural killer (NK) cells. The unique in vitro specificity of NK cells for tumor cells, however, does not explain the specific rejection of bone marrow grafts by NK cells. Recent experiments have implicated antibody in marrow graft recipients as the specificity-inducing component that guides NK cells in an antibody-dependent cytotoxic (ADCC) reaction to attack the marrow graft. On the basis of this hypothesis, one would postulate that nonresponder marrow graft recipients can be converted into responders by injection with antibody of appropriate specificity. Results presented in this report show that this is indeed possible. Specific monoclonal or polyclonal antibody of IgG isotype induces marrow graft rejection in nonresponder recipients. This can be demonstrated in allogeneic as well as in semi-allogeneic (hybrid resistance) donor-recipient strain combinations. Antibody-induced marrow graft rejection is independent of complement and dependent on the presence of NK cells. Surprisingly, graft rejection induced by antibody is quite efficient in allogeneic and semiallogeneic marrow donor-recipient combinations, whereas it is generally poor in syngeneic combinations. This result is not understood if NK cells lyse bone marrow cells solely in an ADCC-type reaction. Because NK cells can lyse targets in an antibody-dependent as well as independent reaction, it is proposed that the binding of NK cells to targets via their receptors plays an additional role in the rejection of bone marrow in vivo. Preliminary evidence for this possibility is that NK cells in the apparent absence of antibody may have a detectable suppressive effect on the growth of marrow grafts in F1 hybrid mice transplanted with parental marrow grafts.
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Ruers, T. J., W. A. Buurman, C. J. van Boxtel, C. J. van der Linden, and G. Kootstra. "Immunohistological observations in rat kidney allografts after local steroid administration." Journal of Experimental Medicine 166, no. 5 (November 1, 1987): 1205–20. http://dx.doi.org/10.1084/jem.166.5.1205.
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In this report we investigated local regulatory mechanisms in graft rejection and their response to local immunosuppressive therapy. For this purpose local immunosuppression was induced in rat kidney allografts by intrarenal infusion of prednisolone. Intrarenal drug delivery resulted in high drug levels within the graft and low systemic drug levels. Systemic drug levels were by themselves not sufficiently immunosuppressive to induce graft survival, and local prednisolone levels within the graft proved to be responsible for prolongation of graft survival. During intrarenal drug delivery, systemic responsiveness to the renal allograft proved normal, since intrarenally treated grafts were infiltrated by MHC class II-positive host cells and, except for a somewhat lower percentage of macrophages, cellular infiltration in intrarenal treated grafts was comparable to untreated grafts. However, T cells and macrophages present in intrarenally treated grafts were not able to destroy the grafted tissue. Local immunosuppressive therapy resulted in inhibition of IL-2-R expression, absence of IFN-gamma, and prevention of MHC class II induction on grafted tissue. These observations strongly indicate the presence of local regulatory mechanisms in graft rejection. The experimental model described can be used for further analysis of these intragraft events. Moreover, the results demonstrate that local immunosuppressive therapy can contribute to effective inhibition of cellular immune response in graft rejection.
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Rijkelijkhuizen, Josephine K. R. A., Annemiek Töns, Onno T. Terpstra, and Eelco Bouwman. "Transplantation of Long-term Cultured Porcine Islets in the Rat: Prolonged Graft Survival and Recipient Growth on Reduced Immunosuppression." Cell Transplantation 19, no. 4 (April 2010): 387–98. http://dx.doi.org/10.3727/096368909x484257.
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To evaluate whether further improvement in porcine islet xenotransplantation is feasible, a number of questions were addressed. Earlier we showed significant improvement in the nude mouse of the porcine islets by selection through long-term culture. Now these islets were tested in the stringent pig-to-rat model. Islets were isolated from adult pigs, cultured for 1.5–3 weeks and transplanted to rats. Possible rejection mechanisms were assessed by interference of the cellular response with cyclosporine A (CsA), blocking macrophages with gadolinium chloride (GdCl), and suppressing the humoral response with cyclophosphamide. Modifications in graft size and condition were analyzed. Untreated control recipients showed primary nonfunction (PNF). CsA treatment could fully overcome PNF and resulted in graft survival from 10 to over 134 days. Rejection was the main cause of function loss. Although rejection could not be prevented by intensifying the induction therapy, increased maintenance immunosuppression effectively blocked rejection, albeit at the expense of toxicity. Blocking the humoral response was ineffective; all grafts showed PNF. In contrast, depletion of macrophages fully prevented PNF. Combination of GdCl and CsA gave no additional effect, and grafts were rejected between 57 and 162 days. Generally, graft survivals were similar to those reported in the literature; however, long-term cultured islets required much less maintenance immunosuppression. Cessation of graft function was not always due to rejection; in some cases “islet exhaustion” was found, possibly caused by discrepancy between the graft size and the rapidly growing recipient. Neither the presence of damaged islet tissue in the graft nor the size of the graft exerted any influence on graft survival. On rejection, no real infiltration of the graft was seen; destruction gradually processed from the outside. The good functional capability of the cultured islets was illustrated by disappearance of the clinical symptoms and increase in body weight, which almost doubled in the long-term survivors.
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Sayin, Ismail, Jacqueline Oien, Deepjyoti Ghosh, Dengping Yin, Madeleine S. Durkee, Peter T. Sage, Marcus R. Clark, and Anita S. F. Chong. "Loss of autoreactive B cell tolerance and production of autoantibodies in chronic kidney allograft rejection in mice." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 173.39. http://dx.doi.org/10.4049/jimmunol.210.supp.173.39.
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Abstract Loss of autoreactive B cell tolerance and production of autoantibodies have been observed in patients undergoing chronic rejection. However, how autoreactive B cells lose their tolerance, and the role of autoreactive antibodies in chronic rejection remains an enigma. Recent observations from our laboratory that autoreactive B cells with a transcriptome profile of innate B cells accumulate in transplanted kidneys diagnosed with antibody-mediated rejection led us to hypothesize that (i) the loss of autoreactive B cell tolerance occurs primarily in the inflamed kidney and (ii) autoantibodies are contributing to graft rejection. In this study, we developed acute and chronic mouse kidney transplant models to test these hypotheses. Donor-specific antibody responses were assayed using donor MHC coated multiplex beads. Autoantibodies were detected with Hep-2 autoantibody detection kit and quantified with an image analysis pipeline in CellProfiler. The presence of autoantibody secreting cells was confirmed by graft tissue culture, and accumulation of autoreactive B cells was confirmed by ex vivo Nojima cultures. We found that autoantibodies were produced during chronic and acute kidney allograft rejection, even when donor MHC-specific antibody was inhibited with CTLA-4Ig. Remarkably, autoantibodies specific for cytoplasmic, nuclear and nucleolar antigens dynamically changed over time, suggesting rapid epitope spreading. Furthermore, there was an enrichment of autoreactive B cells and autoantibody secreting cells in the graft. Taken together, our mouse models complement data from rejecting biopsies, demonstrating a loss of autoreactive B cell tolerance and accumulation of autoantibodies within rejecting allografts. Supported by grant from NIH R01AI148705
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Paunicka, Kathryn, and Jerry Niederkorn. "Penetrating keratoplasty to one eye abolishes immune privilege for corneal allograft placed into the other eye. (P2164)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 69.20. http://dx.doi.org/10.4049/jimmunol.190.supp.69.20.
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Abstract Corneal transplants are the most common and successful form of solid tissue transplantation due to the immune privilege (IP) of the eye. In a mouse model of corneal transplantation, 50% of BALB/c recipients normally accept C57BL/6 (B6) corneal allografts. However, BALB/c recipients that previously rejected an A/J or C3H corneal allograft in the right eye experienced 100% graft rejection of the unrelated B6 corneal allograft. This high incidence of rejection was observed when the B6 allograft placed into either the rejected or the unmanipulated eye. Moreover, BALB/c recipients that previously accepted a BALB/c syngeneic corneal graft on the right eye still had a high rejection rate of B6 grafts placed onto the unmanipulated eye. Thus, surgical manipulation performed during the grafting process causes the loss of IP in the unmanipulated eye. A circumferential corneal surface incision that damages the nerves in the left eye resulted in 100% rejection of B6 grafts placed onto the right eye. This incision upregulated the immunoregulatory neuropeptide Substance P (SP) in both eyes. In vivo blockade of SP with Spantide II reduced graft rejection. Direct injection of SP into the eye recapitulated the trephine effect and results in 90% rejection in both eyes. Circumferential incisions of the corneal surface upregulates SP and promotes graft rejection in repeat corneal allograft recipients.
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Zaman, K., and K. Borah. "Myringoplasty with three meatal flaps." Journal of Laryngology & Otology 102, no. 9 (September 1988): 777–78. http://dx.doi.org/10.1017/s0022215100106413.
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AbstractA preliminary report on a technique of myringoplasty is presented with the idea of minimizing graft rejection, and to combat anterior blunting and lateralization of the graft. The grafts were generally stable and mobile. Out of 200 cases there was only a 2 per cent rate of graft rejection, with no evidence of anterior blunting or lateralization. The hearing improved considerably. The technique is simple and relatively quick.
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Chain, Robert, Marita Chakhtoura, and Stefania Gallucci. "The role of myeloid cells in graft rejection (TRAN3P.893)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 202.32. http://dx.doi.org/10.4049/jimmunol.192.supp.202.32.
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Abstract Acceptance of a mismatched graft is achieved through immunosuppression that requires long-term treatment. A variety of methods have been explored to prevent rejection and achieve transplant tolerance in mouse models. The combination of LPS from gram-negative Bacteria, and tissue damage from the transplant procedure has been suggested to prevent rejection and deserves further investigation. We implemented a mouse skin transplant model to determine the effects of LPS and endogenous danger signals released during engraftment, on myeloid cell functions and study their ability to induce rejection or tolerance in transplantation. We used the spontaneous single minor histocompatibility mismatch model of skin graft rejection and performed skin grafts from male mice onto syngeneic female recipients then treated the mice with LPS or PBS. Control mice completely rejected the graft between 24-34 days, while mice treated with LPS did not show graft rejection until an average of 64 days, with 50% graft acceptance. When we studied the graft immune infiltrate, we found that within 48 hours post transplantation, there was an influx of GR-1+ CD11b+ double positive cells. LPS-treated recipients showed a significant decrease in the recruitment of these GR-1+ CD11b+ double positive cells at the graft site. These results indicate that GR-1+ CD11b+ myeloid cells migrate to the site of transplantation following trauma and suggest they play a key role in graft rejection, warranting further study.
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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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Bicalho, Paula Rebello, Lúcio R. Requião-Moura, Érika Ferraz Arruda, Rogerio Chinen, Luciana Mello, Ana Paula F. Bertocchi, Erika Lamkowski Naka, Eduardo José Tonato, and Alvaro Pacheco-Silva. "Long-Term Outcomes among Kidney Transplant Recipients and after Graft Failure: A Single-Center Cohort Study in Brazil." BioMed Research International 2019 (April 2, 2019): 1–10. http://dx.doi.org/10.1155/2019/7105084.
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Background. The results of kidney transplantation are impacted by the categories of events responsible for patient death and graft failure. The objective of this study was to evaluate the causes of death and graft failure and outcomes after graft failure among kidney transplant recipients. Methodology. A retrospective cohort study was conducted with 944 patients who underwent kidney transplantation. Outcomes were categorized in a managed and hierarchical manner. Results. The crude mortality rate was 10.8% (n=102): in 35.3% cause of death was infection, in 30.4% cardiovascular disease, and in 15.7% neoplasia and in 6.8%, it was not possible to determine the cause of death. The rate of graft loss was 10.6%. The main causes of graft failure were chronic rejection (40%), acute rejection (18.3%), thrombosis (17.3%), and recurrence of primary disease (16.5%). Failures due to an acute rejection occurred earlier than those due to chronic rejection and recurrence (p<0.0001). As late causes of graft loss, death with the functioning kidney occurred earlier than recurrence and chronic rejection (p=0.008). The outcomes after graft failure were retransplantation in 26.1% and death in 21.4%, at a mean of 25.5 and 21.4 months, respectively. Conclusion. It was possible to identify more than 90% of the events responsible for the deaths of transplanted patients, predominantly infectious and cardiovascular diseases. Among the causes of graft failure, chronic and acute rejections and recurrence were the main causes of graft failure which were followed more frequently by retransplantation than by death on dialysis.
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Isakov, N., and F. H. Bach. "Participation of class II alloantigens in in vivo regulation of K/D region disparate thyroid graft rejection in mice." Journal of Immunology 134, no. 6 (June 1, 1985): 3580–85. http://dx.doi.org/10.4049/jimmunol.134.6.3580.
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Abstract Class I and II molecules preferentially activate cytotoxic T cells and helper T cells, respectively, in primary in vitro alloactivation of T lymphocytes. Collaboration between these subpopulations leads to an efficient anti-class I specific cytotoxic response. We tested whether the presence of class II, in addition to class I, alloantigens on thyroid allografts in vivo induces augmentation of anti-class I antigen immune response and leads to rejection of K/D region disparate grafts which otherwise would have been accepted. Different pairs of K or D region disparate mouse strains were selected in which transplantation across a class I antigen disparity alone resulted in long-term graft acceptance. In some pairs of mouse strains, co-transplantation of recipient mice with a second thyroid graft sharing the K/D region of the first, but additionally expressing an allo class II molecule, led to accelerated K/D region disparate thyroid graft rejection. Transplantation of thyroid allografts expressing both class II and I alloantigens did not induce increased host anti-class I antigen cytotoxic response, or affect the frequency of specific precursor cytotoxic T cells. In one pair of congenic mouse strains, acute rejection of K/D region disparate thyroid grafts occurred in the absence of class II alloantigen stimulation; in other strains, co-transplantation of class I and II alloantigen disparate thyroid allografts was not sufficient to induce K/D region disparate graft rejection. The results thus demonstrate that a class II alloantigen on a thyroid graft may augment the rejection response directed against the graft class I alloantigens. The class II alloantigen stimulation was not always essential or sufficient for induction of class I antigen disparate thyroid graft rejection, and was dependent on the specific I region and/or K/D region gene allele.
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Yankelevich, B., C. Knobloch, M. Nowicki, and G. Dennert. "A novel cell type responsible for marrow graft rejection in mice. T cells with NK phenotype cause acute rejection of marrow grafts." Journal of Immunology 142, no. 10 (May 15, 1989): 3423–30. http://dx.doi.org/10.4049/jimmunol.142.10.3423.
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Abstract Acute rejection of allogeneic and semiallogeneic marrow grafts has long been considered to be a function of the natural immune system because it shares many features with NK activity in mice. With the use of a recently developed in vivo adoptive transfer assay in which spleen cells are transferred from mice able to reject a particular marrow graft into mice that fail to do so, we show that the cells responsible for induction of marrow graft rejection indeed display the phenotype of NK cells: they lack the T cell Ag CD4 and CD8 but express the NK Ag NK1 and ASGM1. The rejection induced by adoptively transferred cells is exquisitely specific--a feature that points to a specific recognition process by the transferred cells. To elucidate what the recognition structure on these cells may be we found that they express CD3 and most likely the beta-chain of the TCR. Highly purified responder cells with the NK1+, CD3+, CD4-, CD8- phenotype, when transferred into nonresponder recipients, cause specific marrow graft rejection. We conclude that the acute rejection of bone marrow grafts is caused by a cell that expresses NK phenotype but is of T cell lineage. This may suggest the specificity of acute marrow graft rejection is caused by a specific recognition process that involves TCR.
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Pavlakis, M., M. L. Lipman, and T. B. Strom. "Intragraft T cell receptor transcript expression in human renal allografts." Journal of the American Society of Nephrology 6, no. 2 (August 1995): 281–85. http://dx.doi.org/10.1681/asn.v62281.
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Allograft rejection is a T cell-dependent process. It is not known whether rejection is mediated by a limited number of T cell clones or by a polyclonal population of T cells. Several studies attempting to answer this question using molecular techniques to analyze the T cell receptor (TCR) population have reached conflicting conclusions. Reverse transcription-assisted polymerase chain reaction (PCR) has been used to quantify T cell infiltration and examine TCR heterogeneity in kidney transplant biopsies from patients experiencing graft dysfunction. RNA from snap-frozen biopsies gathered on 23 transplant patients was reverse transcribed to cDNA and used as the template for PCR. The constant region gene of the TCR beta chain (C beta), 22 different variable region genes of the TCR beta chain (V beta) and the constitutively expressed glyceraldehyde phosphate dehydrogenase (GAPD) gene were amplified. T cell infiltration, as estimated by the ratio of reverse-transcribed cDNA C beta/glyceraldehyde phosphate dehydrogenase, was significantly higher in acute cellular rejection (ACR) (2.25) than in nonrejection (NR) (0.40, P < 0.05). The number of intragraft V beta families was higher in chronic rejection and acute cellular rejection (18 and 16.4, respectively) than in nonrejection (8.7). Five serial biopsies from two patients progressing to immunologic graft loss showed an increase in the number of intragraft V beta families. The finding of increased numbers of TCR V beta families amplified from acutely and chronically rejecting grafts as compared with nonrejecting graft supports the hypothesis that, at the time of clinically apparent rejection, there is a polyclonal infilitration of T cells.
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Graca, Luis, Stephen P. Cobbold, and Herman Waldmann. "Identification of Regulatory T Cells in Tolerated Allografts." Journal of Experimental Medicine 195, no. 12 (June 10, 2002): 1641–46. http://dx.doi.org/10.1084/jem.20012097.
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Induction of transplantation tolerance with certain therapeutic nondepleting monoclonal antibodies can lead to a robust state of peripheral “dominant” tolerance. Regulatory CD4+ T cells, which mediate this form of “dominant” tolerance, can be isolated from spleens of tolerant animals. To determine whether there were any extra-lymphoid sites that might harbor regulatory T cells we sought their presence in tolerated skin allografts and in normal skin. When tolerated skin grafts are retransplanted onto T cell–depleted hosts, graft-infiltrating T cells exit the graft and recolonize the new host. These colonizing T cells can be shown to contain members with regulatory function, as they can prevent nontolerant lymphocytes from rejecting fresh skin allografts, without hindrance of rejection of third party skin. Our results suggest that T cell suppression of graft rejection is an active process that operates beyond secondary lymphoid tissue, and involves the persistent presence of regulatory T cells at the site of the tolerated transplant.
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Gracie, J. A., E. M. Bolton, C. Porteous, and J. A. Bradley. "T cell requirements for the rejection of renal allografts bearing an isolated class I MHC disparity." Journal of Experimental Medicine 172, no. 6 (December 1, 1990): 1547–57. http://dx.doi.org/10.1084/jem.172.6.1547.
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This study has examined the cellular and humoral responses underlying the rejection of rat renal allografts bearing an isolated RT1Aa class I MHC disparity. RT1Aa disparate kidneys were rejected promptly by high responder RT1u but not by low responder RT1c recipients (median survival time 10 d and greater than 100 d, respectively). The magnitude and phenotype of the cellular infiltrate were similar in rejecting and nonrejecting RT1Aa disparate kidneys. Paradoxically, graft infiltrating cells and spleen cells from RT1u recipients showed minimal ability to lyse donor strain lymphoblasts in vitro, whereas effector cells from RT1c recipients showed modest levels of cytotoxicity. Injection of RT1u rats with MRC OX8 mAb was highly effective at selectively depleting CD8+ cells from graft recipients but had no effect in prolonging the survival of RT1Aa disparate grafts despite the complete absence of CD8+ cells from the graft infiltrate, which included numerous CD4+ T cells and macrophages. RT1u, but not RT1c, recipients mounted a strong alloantibody response against RT1Aa disparate kidneys. Immune serum obtained from RT1u recipients that had rejected a RT1Aa disparate graft was able, when injected into cyclosporin-treated RT1u recipients, to restore their ability to reject a RT1Aa, but not a third-party RT1c, kidney. These results suggest that CD8+ cells in general and CD8+ cytotoxic effector cells in particular are unnecessary for the rapid rejection of RT1Aa class I disparate kidney grafts by high responder RT1u recipients. By implication, CD4+ T cells alone are sufficient to cause prompt rejection of such grafts and they may do so by providing T cell help for the generation of alloantibody.
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Kuligowski, Michael, Yik Loh, Rain Kwan, and Barbara de St Groth. "Multiphoton intravital microscopy visualization of skin graft rejection in real time (126.14)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 126.14. http://dx.doi.org/10.4049/jimmunol.188.supp.126.14.
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Abstract The current paradigm explaining organ graft rejection postulates that rejection is initiated by graft resident dendritic cells that reach the draining lymph nodes via lymphatics and activate naive alloreactive T cells. These newly activated T cells then migrate into the graft. However up to half the T cells recognizing allogeneic MHC in adult animals are already be of memory phenotype, and thus capable of direct entry into a graft site without prior activation in LNs. This is not the result of previous exposure to allo-Ag, but stems from the fact that the allo-MHC-specific and Ag-specific T cell receptor repertoires overlap each other. These pre-existing allo-reactive T cells represent a major barrier to organ transplantation. To understand the contributions of memory cells to skin graft rejection, we are using intravital multiphoton microscopy to track cellular interactions between memory cells, DCs and lymphatic and vascular endothelium during graft rejection and acceptance. Preliminary studies suggest that DCs from grafts are unable to exit the surgical site, most likely as a result of surgical disruption of lymphatic drainage from the transplanted skin. Further work will investigate trafficking of graft-reactive CD4 effector and Treg cells into the graft site.
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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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Mandal, Sohini, Prafulla K. Maharana, Luci Kaweri, Mohamed I. Asif, Ritu Nagpal, and Namrata Sharma. "Management and prevention of corneal graft rejection." Indian Journal of Ophthalmology 71, no. 9 (August 21, 2023): 3149–59. http://dx.doi.org/10.4103/ijo.ijo_228_23.
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The management of an episode of corneal graft rejection (CGR) is primarily by corticosteroids. Immunomodulators are useful for long-term immunosuppression and in dealing with cases of high-risk (HR) corneal grafts. The classical signs of CGR following penetrating keratoplasty (PKP) include rejection line, anterior chamber (AC) reaction, and graft edema. However, these signs may be absent or subtle in cases of endothelial keratoplasty (EK). Prevention of an episode of graft rejection is of utmost importance as it can reduce the need for donor cornea significantly. In our previous article (IJO_2866_22), we had discussed about the immunopathogenesis of CGR. In this review article, we aim to discuss the various clinical aspects and management of CGR.
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Hall, B. M., M. E. Jelbart, K. E. Gurley, and S. E. Dorsch. "Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells." Journal of Experimental Medicine 162, no. 5 (November 1, 1985): 1683–94. http://dx.doi.org/10.1084/jem.162.5.1683.
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DA rats grafted with major histocompatibility complex-incompatible PVG heart grafts and treated with cyclosporine (CY) for 10 d do not reject their grafts, and develop a state of specific unresponsiveness toward PVG allografts. Cells from these animals tested in an adoptive transfer assay were incapable of restoring PVG graft rejection, and capable of specifically inhibiting the capacity of adoptively transferred normal lymph node cells (LNC) to do so. They effected third party Wistar/Furth (W/F) graft rejection, however. Adoptive transfer assays with purified subpopulations of the lymphocytes that mediated this effect showed that W3/25+ T cells of the helper/inducer subclass, when injected alone, failed to restore rejection, and were also able, when injected with normal LNC or the W/25+ cells separated from them, to prevent these cells from effecting rejection. MRC OX8+ T cells of the cytotoxic/suppressor subclass, B cells, and serum from rats with long-surviving grafts all failed to inhibit the allograft responsiveness of normal LNC, and thus were not identified as mediators of the state of specific unresponsiveness. These results show that the specific unresponsiveness that develops in rats with long-surviving grafts, and which, in part at least, is responsible for prolonged graft survival, is due to an alteration in the alloreactivity of the helper/inducer subclass of T cells. These cells not only lack the capacity to initiate a rejection response against the alloantigens of the graft, but also have the ability to inhibit the capacity of normal W3/25+ cells to do so.
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Saarinen, O., K. Salmela, J. Ahonen, and J. Edgren. "Reversed Diastolic Blood Flow at Duplex Doppler." Acta Radiologica 35, no. 1 (January 1994): 10–14. http://dx.doi.org/10.1177/028418519403500103.
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In 25 renal allografts out of 253 with graft dysfunction a reversed diastolic blood flow was observed at duplex ultrasonography during the first post-transplant month. Eleven grafts were lost and 14 survived. The cause of graft loss was arterial thrombosis (n = 1), venous thrombosis or obstruction (n = 4), steroid resistant acute rejection (n = 4) and acute tubular necrosis (ATN) (n = 2). The cause of graft dysfunction in the surviving grafts was ATN (n = 7) and acute allograft rejection (n = 7). Grafts with only peak-like or low velocity continuous diastolic flow reversal had a better prognosis (3 out of 15 were lost) than grafts with any other type of reversed flow pattern (8 out of 10 were lost). This difference was statistically significant (p < 0.01).
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Mathews, Vikram, Abhijeet Ganapule, Biju George, Kavitha M. Lakshmi, Aby Abraham, Auro Viswabandya, and Alok Srivastava. "Clinical Profile and Outcome Of Patients With Graft Rejection Following Related HLA Matched Allogeneic Stem Cell Transplant For β Thalassemia Major." Blood 122, no. 21 (November 15, 2013): 4546. http://dx.doi.org/10.1182/blood.v122.21.4546.4546.
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Allogeneic stem cell transplant (SCT) remains the only curative option for patients with β thalassemia major (TM). Graft rejections post SCT are unfortunately a common problem in this condition. There is limited data on the clinical profile and long term outcome of patients who have had a graft rejection post allogeneic SCT. We undertook a retrospective analysis of patients who had a graft failure post allogeneic SCT for TM at our center. From October, 1991 to April, 2013, 400 HLA matched related transplants for TM was done at our center. The median age was 8 years (range: 1-24) and there were 250 (62.5%) males. 154 (38.5%) were Lucarelli Class II and 229 (57.2%) were in the Class III risk group. Majority (72%) received a busulfan based conditioning regimen while 22% received a treosulfan based regimen. Bone marrow was the source of stem cells in 81% and PBSC in the rest. Majority of the patients received a CSA plus short course methotrexate GVHD prophylaxis regimen. There were 48 (12%) graft rejections in this cohort. Among these 26 (54%) were primary graft failures (PGF) while 22 (46%) were secondary graft failures (SGF). The median time to a secondary graft failure was 122 days (range: 40 - 2210). Of the 26 PGF, 9(34.6%) had autologous recovery with recurrence of transfusion dependence while 17(65.4%) had pancytopenia. 11 (42.3%) of PGF died prior to second transplant, 10 had a second transplant and 3(11.53%) had recurrence of TM but were alive and well. Among the 22 SGF, 10(45.5%) had autologous recovery. Of the SGF, 2 died prior to a second transplant while 9 had a second transplant and the remaining (n=11) had recurrence of TM and were on conservative management. Among the 29 cases that did not receive a second transplant 14 died at a median time of 20 days from date of documented rejection (range: 0-3268). The major cause of death in this group was graft failure with infection (n=10) and regimen related toxicity (RRT; N=4). Of the remaining cases, 14 have recurrent TM and are alive and well on conservative management while one patient is alive with pancytopenia and is transfusion dependent. 19 (39%) of the patients with graft rejection underwent a second allogeneic SCT. The median time from graft rejection to second transplant was 6 months (range: 0-42). Conditioning regimen for second SCT was busulfan based in 5 (26.3%), treosulfan based in 5 (26.3%) and the remaining received non-myeloablative conditioning regimens (fludarabine based, low dose TBI, OKT3, Cy-OKT3) in view of pancytopenia. The source of stem cells was BM in 7(36.84%) and PBSC in the rest. All cases conditioned with treosulfan based regimen received a PBSC graft. The OS and EFS of the patients that had a second transplant was 41.4±12.8% and 37.6±12.2% respectively. None of the patients conditioned with a treosulfan based regimen died or had a second graft rejection (data summarized in table 1). Of the remaining 14 patients 11 died of second graft rejection while 3 (all busulfan based conditioning) are alive and well at 3, 23 and 81 months from second transplant.Table 1Clinical profile and outcome of patients with graft rejections who underwent a second allogeneic SCT with a treosulfan based conditioning regimen and PBSC graft. All patients engrafted and are alive and transfusions independent at last follow upSerial NoAge (years)SexLiver size (cms)Lucarelli ClassStem cell dose (x10E6/kg)Acute GVHDChronic GVHDLast follow up (mths)17M2310.34NILYes10.422M4213.7NILNIL3.635M4310NILNIL3.6418M2310Grade 4NIL4.9518M13315NILNIL2.9 In conclusion graft rejection following allogeneic SCT for patients with TM are associated with poor clinical outcomes. Following a second transplant there is a high incidence of deaths due second graft rejection and infections. A treosulfan based reduced toxicity myeloablative regimen with a PBSC graft has potential to significantly improve the outcome in this group of patients. Disclosures: No relevant conflicts of interest to declare.
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Atif, Shaikh M., Sophie L. Gibbings, Ronald G. Gill, Kenneth M. Murphy, Todd Grazia, Raul M. Torres, Peter M. Henson, Gwendalyn J. Randolph, and Claudia Jakubzick. "Coordinated immune activation by distinct mononuclear phagocytes subtypes against the mismatch of minor antigens." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 116.14. http://dx.doi.org/10.4049/jimmunol.196.supp.116.14.
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Abstract Recently, we identified that Batf3-dependent DCs were solely responsible for the rejection of minor antigen-mismatched grafts, and demonstrated in Batf3−/− female mice, lacking Batf3-dependent DCs, the complete acceptance of minor antigen-mismatched male cells, which are normally rejected in WT female mice. Intriguingly, this rejection occurs in the absence of PAMPs, leading to considerable uncertainty of how endogenous APC subtypes become activated and licensed to induce an adaptive immune response against male cells in female mice. Investigating this gap in knowledge is the main goal of this study. Rejection of minor antigen-mismatched grafts involves all branches of the immune system: adaptive immunity (T cells), humoral immunity (B cells) and innate immunity (DCs and antigen-presenting monocytes). Although we showed that depletion of one cell type dampens or omits the inflammatory outcome of minor antigen-mismatched graft rejection, here we show how lymphoid and myeloid cell subtypes act sequentially and in concert for the induction of minor antigen-mismatched graft rejection without the presence of PAMPs. In conclusion, we believe that understanding the mechanisms of action against minor antigen-mismatched graft rejection will also apply more broadly to other diseases such as autoimmunity and cancer, in which an immune response is elicited against self-associated minor antigens.
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Emmerich, Florian, Stefan Zschiedrich, Christine Reichenbach-Braun, Caner Süsal, Susana Minguet, Marie-Christin Pauly, and Maximilian Seidl. "Low Pre-Transplant Caveolin-1 Serum Concentrations Are Associated with Acute Cellular Tubulointerstitial Rejection in Kidney Transplantation." Molecules 26, no. 9 (April 30, 2021): 2648. http://dx.doi.org/10.3390/molecules26092648.
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Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote the survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pre-transplant serum concentrations of Cav-1 and the occurrence of rejection during follow-up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute cellular tubulointerstitial rejection episodes.
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Makra, Zita, Tamás Tuboly, and Gábor Bodó. "Penetrating keratoplasty and graft rejection in eight horses." Acta Veterinaria Hungarica 61, no. 2 (June 1, 2013): 160–74. http://dx.doi.org/10.1556/avet.2013.002.
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The aim of this study was to describe long-term follow-up and difference in immune reactions in the tear film following penetrating keratoplasty (PK) in horses when differently preserved corneas were utilised. This report describes for the first time the use of corneal grafts preserved in tissue culture media in equine PK. Eight experimental horses with normal eyes were included and freshly harvested, frozen or preserved corneal grafts were used for the PK. The graft-taking technique and storage, PK surgery, postoperative treatments and complications are described. The mean postoperative follow-up time was 286 days. Tear film samples taken before and periodically after surgery were measured for IgM, IgG and IgA contents by direct ELISA. All grafts were incorporated into the donor horse but were rejected to some degree. The differently harvested corneal grafts healed in the same manner and looked similar. Preoperatively, the clear corneas meant low risk for graft failure, and the fresh or stored tissues provided intact endothelium, although there were no clear graft sites postoperatively. The presence of IgA, IgG and IgM was demonstrated in the tear film from the early postoperative period. IgG levels were lower than IgA or IgM and had a constant baseline in every case, as IgA and IgM had great variability with time and an individual pattern in each eye.
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Gerull, Sabine, Joerg Halter, Christoph Bucher, Dominik Heim, André Tichelli, Alois Gratwohl, and Martin Stern. "Cyclosporine Levels and Rate of Graft Rejection Following Reduced Intensity Conditioning." Blood 114, no. 22 (November 20, 2009): 3337. http://dx.doi.org/10.1182/blood.v114.22.3337.3337.
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Abstract Abstract 3337 Poster Board III-225 In the past decade there has been a significant increase in the use of reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (HSCT). RIC HSCT is associated with reduced transplant related mortality, but also with an increased risk of relapse and graft rejection. Little is known about factors associated with graft rejection. Based on early animal models, intensified cyclosporine (CyA) administration is considered an essential component of RIC HSCT with minimal conditioning. We were interested in analyzing the role of CyA in graft rejection following RIC HSCT. Between October 1999 and December 2008, 85 patients received an allogeneic RIC HSCT with fludarabine 3 × 30 mg/m2 and 2 Gy TBI as conditioning at our institution. 6 patients were excluded from the analysis due to graft loss associated with relapse or progressive disease, 2 were excluded for missing data. Diseases were acute leukemia (N=19), MDS (N=11), CML/MPN (N=10), lymphoma (N=24), multiple myeloma (N=12), and pure white cell aplasia (N=1). Donors were HLA-identical siblings (N=54) or unrelated donors (N=23). Graft source was peripheral blood (N=74) or bone marrow (N=3). Graft-versus-host disease (GvHD) prophylaxis consisted of CyA and mycophenolate mofetil (MMF). CyA was started at a dose of 6.25mg/kg p.o. twice daily and adjusted according to trough levels (measured weekly) and toxicity. MMF was administered at a dose of 15mg/kg twice daily; trough levels were not analyzed systematically. For the analysis of impact on graft rejection, CyA levels between day 1 and 28 where summarized as mean trough levels. Graft rejection was defined as <5% donor cells at any time on day 28 or later or application of donor lymphocyte infusion for declining donor chimerism. Of the 77 evaluable patients, 16 (21%) experienced graft rejection at a median of 69 days after transplantation. There was no significant difference in disease stage (early vs. advanced), median age at transplant (56 and 57 years, respectively), EBMT risk score, graft cell count (nucleated and CD34+ cells) and history of previous transplants between patients with or without rejection. In contrast, there was a significant difference in underlying disease, with a higher proportion of CML/MPN and a lower proportion of multiple myeloma in rejecting patients. Mean CyA trough levels were clearly associated with graft rejection with a cumulative incidence of rejection of 8%, 29% and 56% with trough levels of <300 ng/ml (N=40), 300-600 ng/ml (N=28) and >600 ng/ml (N=9) (p=0.002) (Figure A) and a median donor chimerism at day 28 of 99%, 84%, and 72% respectively (p=0.004). In a multivariate analysis, two factors remained significantly associated with graft rejection: unrelated donor (HR vs. sibling donor 4.52, p = 0.03), and mean trough level of CyA for days 1-28 (HR 1.006 per ng/ml increase, p=0.001). Patients with CML/MPN had an increased risk of rejection (HR 1.36 versus other patients combined, p=0.65) which did not reach statistical significance. The overall survival of the entire patient group was 55% at five years; patients with stable engraftment had a five-year survival rate of 61%, those rejecting their graft 36% (p=0.04). These data indicate that elevated CyA levels during the first month posttransplant might be associated with an increased risk of graft rejection. The potentially detrimental effects of high CyA levels have been described previously in the myeloablative setting, where a correlation between CyA levels and risk of relapse has been shown. Further studies will be needed to better define the exact role of CyA following RIC regimens. Disclosures Gratwohl: Amgen: Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.
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Harooni, Hooman, Vandana Reddy, Timothy Root, and Balamurali Ambati. "Bevacizumab for Graft Rejection." Ophthalmology 114, no. 10 (October 2007): 1950–1950. http://dx.doi.org/10.1016/j.ophtha.2007.05.016.
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Polack, Frank M. "Graft Rejection and Glaucoma." American Journal of Ophthalmology 101, no. 3 (March 1986): 294–97. http://dx.doi.org/10.1016/0002-9394(86)90822-6.
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Simpson, S. J. "IMMUNOLOGY: Regulating Graft Rejection." Science 297, no. 5578 (July 5, 2002): 17a—17. http://dx.doi.org/10.1126/science.297.5578.17a.
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Andersen, CLAUS B., SØREN D. Ladefoged, and SVEND Larsen. "Acute kidney graft rejection." APMIS 102, no. 1-6 (January 1994): 23–37. http://dx.doi.org/10.1111/j.1699-0463.1994.tb04841.x.
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Goyal, Sunali, and Sami H. Uwaydat. "Multiquadrant Subtenon Triamcinolone Injection for Acute Corneal Graft Rejection: A Case Report." Case Reports in Ophthalmology 8, no. 2 (May 29, 2017): 308–13. http://dx.doi.org/10.1159/000477202.
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Background: We report a case of reversal of an acute corneal graft rejection following multiquadrant subtenon triamcinolone injection. Case Presentation: A 19-year-old woman who had acute corneal graft rejection failed to show resolution of the graft rejection after standard treatment with systemic, intravenous, and topical steroids. The graft rejection, however, responded to injection of triamcinolone in multiple subtenon quadrants. Conclusions: For corneal graft rejection, multiquadrant subtenon triamcinolone injections may be a safe adjunct to systemic treatment.
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GRIMM, PAUL C., RACHEL MCKENNA, PETER NICKERSON, MARY E. RUSSELL, JIM GOUGH, ELZBIETA GOSPODAREK, BIN LIU, JOHN JEFFERY, and DAVID N. RUSH. "Clinical Rejection Is Distinguished from Subclinical Rejection by Increased Infiltration by a Population of Activated Macrophages." Journal of the American Society of Nephrology 10, no. 7 (July 1999): 1582–89. http://dx.doi.org/10.1681/asn.v1071582.
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Abstract. It has been reported previously that one-third of protocol renal biopsies in asymptomatic, biochemically stable renal transplant recipients in the first 6 mo show unsuspected subclinical graft rejection (both infiltrate and tubulitis) and that subclinical rejection is a risk factor for chronic renal dysfunction. This study was performed to determine whether differences in phenotype or activation status of graft-infiltrating cells underlie these different manifestations of acute rejection. Biopsies with normal histology (n = 10), subclinical rejection (n = 13), and clinical rejection (n = 9) were studied using immunohistochemistry and computerized image analysis. Subclinical and clinical rejections had similar histologic Banff scores. Univariate analysis showed a trend for a higher infiltration with CD8+ (P = 0.053) and CD68+ (P = 0.06) cells in clinical rejection. Of the activation markers studied (CD25, perforin, tumor necrosis factor-α), only allograft inflammatory factor-1 +-activated macrophages were significantly (P = 0.014) increased in the infiltrate of clinical rejection biopsies. These data suggest that activated macrophages or their products are responsible for acute renal dysfunction associated with clinical rejection episodes.
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McKisic, Maureen D., James D. Macy, Margaret L. Delano, Robert O. Jacoby, Frank X. Paturzo, and Abigail L. Smith. "MOUSE PARVOVIRUS INFECTION POTENTIATES ALLOGENEIC SKIN GRAFT REJECTION AND INDUCES SYNGENEIC GRAFT REJECTION1." Transplantation 65, no. 11 (June 1998): 1436–46. http://dx.doi.org/10.1097/00007890-199806150-00005.
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Smith, Christopher, Daniel Kaitis, Jordan Winegar, Sean Edelstein, Matthew Council, George Kontadakis, Rocio Bentivegna, and Mohamed Abou Shousha. "Comparison of endothelial/Descemet’s membrane complex thickness with endothelial cell density for the diagnosis of corneal transplant rejection." Therapeutic Advances in Ophthalmology 10 (January 2018): 251584141881418. http://dx.doi.org/10.1177/2515841418814187.
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Purpose: This study compared the effectiveness of endothelial/Descemet’s membrane complex thickness obtained using high-definition anterior segment optical coherence tomography with endothelial cell density obtained using confocal microscopy as diagnostic tools in predicting corneal transplant rejection. Methods: This observational, prospective, cross-sectional study evaluated penetrating keratoplasty grafts. Slit lamp examination organized the grafts into healthy or rejecting grafts. Grafts were scanned using both high-definition anterior segment optical coherence tomography and confocal microscopy. Central corneal thickness, endothelial/Descemet’s membrane complex thickness, endothelial cell density, and coefficient of variation were each compared with the clinical status. Descemet’s rejection index, defined by endothelial/Descemet’s membrane complex thickness divided by central corneal thickness multiplied by 33, further compared endothelial/Descemet’s membrane complex thickness with central corneal thickness. Results: Endothelial/Descemet’s membrane complex thickness, central corneal thickness, and Descemet’s rejection index were all able to differentiate between clear and rejected corneal grafts ( p < 0.0001, p = 0.001, and p = 0.012, respectively). Endothelial cell density and coefficient of variation did not correlate with the clinical status ( p = 0.054 and p = 0.102, respectively). Endothelial/Descemet’s membrane complex thickness had the largest area under the curve using receiver operating characteristic curves ( p < 0.0001). Endothelial/Descemet’s membrane complex thickness had a sensitivity of 86% and specificity of 81% with a cutoff value of >16.0 µm ( p < 0.0001). The sensitivity and specificity of endothelial cell density were both 71% with a cutoff value of ⩽897 cells/mm2 ( p = 0.053). There was a high correlation between endothelial/Descemet’s membrane complex thickness and both Descemet’s rejection index and central corneal thickness ( p < 0.0001). Conclusion: Endothelial/Descemet’s membrane complex thickness measured by high-definition anterior segment optical coherence tomography is a useful parameter for the diagnosis of corneal graft rejection. The diagnostic performance of endothelial/Descemet’s membrane complex thickness was significantly better than that of endothelial cell density and central corneal thickness. Endothelial cell density and the coefficient of variation were unable to diagnose corneal graft rejection in our cross-sectional study.
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Burdine, Marie, Zachary Waldrip, and Lyle Burdine. "DNA-PKcs Inhibition Extends Allogeneic Skin Graft Survival." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 28.15. http://dx.doi.org/10.4049/jimmunol.206.supp.28.15.
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Abstract Background: Organ transplantation is life-saving and continued investigations into immunological mechanisms that drive organ rejection are needed to improve immunosuppression therapies and prevent graft failure. DNA-dependent protein kinase catalytic subunit, DNA-PKcs, is a critical component of both the cellular and humoral immune responses. In this study, we investigate the contribution of DNA-PKcs to allogeneic skin graft rejection to potentially highlight a novel strategy for inhibiting transplant rejection. Methods: Fully MHC mismatched murine allogeneic skin graft studies were performed by transplanting skin from BalbC mice to C57bl6 mice and treating with either vehicle or the DNA-PKcs inhibitor NU7441. Graft rejection, cytokine production, immune cell infiltration, and donor-specific antibody (DSA) formation were analyzed. Results: DNA-PKcs inhibition significantly reduced necrosis and extended graft survival compared to controls (mean survival 14 days vs 9 days respectively). Inhibition reduced the production of the cytokines Interleukin (IL)2, IL4, IL6, IL10, TNFα, and IFNγ and the infiltration of CD3+ lymphocytes into grafts. Furthermore, DNA-PKcs inhibition reduced the number of CD19+ B cells and CD19+ CD138+ plasma cells coinciding with a significant reduction in DSAs. At a molecular level, we determined that the immunosuppressive effects of DNA-PKcs inhibition were mediated, in part, via inhibition of NFκB signaling through reduced expression of the p65 subunit. Conclusion: Our data confirm that DNA-PKcs contributes to allogeneic graft rejection and highlight a novel immunological function for DNA-PKcs in the regulation of NFκB and concomitant cytokine production.
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Larsson, Pierre, Bodil Englund, Jana Ekberg, Marie Felldin, Verena Broecker, Lars Mjörnstedt, and Seema Baid-Agrawal. "Difficult-to-Treat Rejections in Kidney Transplant Recipients: Our Experience with Everolimus-Based Quadruple Maintenance Therapy." Journal of Clinical Medicine 12, no. 20 (October 21, 2023): 6667. http://dx.doi.org/10.3390/jcm12206667.
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All chronic and treatment-resistant acute rejections are “difficult-to-treat” and lead to progressive loss of graft function in kidney transplant recipients (KTR), as no effective treatment exists for such rejections to date. We review our experience with a novel strategy to treat such rejections by adding everolimus as a “rescue” to conventional triple maintenance therapy with prednisolone, mycophenolate mofetil and calcineurin inhibitor. We retrospectively analysed data in 28 KTR who received everolimus-based quadruple therapy at our institution for biopsy-proven chronic active T cell-mediated or antibody-mediated rejection (n = 19) or treatment-resistant acute rejections (n = 9) between 2011–2017. The primary outcome was 5-year death-censored graft survival. Main secondary outcomes were response to treatment defined by stable or improved graft function, 5-year patient survival and discontinuation rate of treatment. The Kaplan–Meier estimate for 5-year death-censored graft survival was 79% in all patients, 90% for patients with chronic active T cell-mediated rejections, 78% for chronic active antibody-mediated rejection and 67% for acute rejections. Response to treatment was achieved in 43% and 5-year patient survival was 94%. Treatment was stopped in 12 (43%) patients due to adverse events. Everolimus-based maintenance quadruple therapy, despite high rate of everolimus discontinuation due to adverse events, may be a valid approach in a subset of kidney transplant recipients with such difficult-to-treat rejections, which otherwise would lead to a high rate of graft loss.