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1
Dooldeniya, Mohanta Deevan. "The role of graft expressed Fasligand in graft rejection." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419907.
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Waters, Cheryl Denise. "The cellular requirements for graft rejection." Thesis, The University of Sydney, 1985. https://hdl.handle.net/2123/26737.
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The studies described in this thesis were designed to develop a model in which the capacity of various lymphoid cells subpopulations to cause graft rejection could be tested and correlated with their capacity to effect in vitro lysis of appropriate target cells.
3
Wu, Guosheng. "Experimental studies on xenograft rejection /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4805-4/.
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Patrick, Guy M. "Studies of cytokines in alloimmune responses /." Title page, table of contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09php314.pdf.
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Kumar, Rajesh. "Does graft-expressed TRAIL modify the rejection process?" Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544289.
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Duguid, I. G. M. "Prevention of corneal graft rejection with monoclonal antibodies." Thesis, University of Aberdeen, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387460.
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This thesis aims to place corneal allograft rejection in the context of general transplantation immunology, examine the role of lymphocyte subsets in the rejection process and consider the potential application of monoclonal antibody therapy in clinical corneal graft rejection. The literature relating to the current clinical practice of corneal grafting, with particular reference to corneal allograft rejection, is reviewed in chapter 1 to present the extent of the problem. Chapter 2 then reviews the mechanisms of allograft rejection from the literature of transplantation immunology, much of which has arisen from studies of kidney, heart, pancreatic islets and liver in animal models. The materials and methods are described in detail in chapter 3, and only the relevant experimental design is detailed in the Materials and Methods sections of the succeeding chapters. The experimental mouse model of transplanting corneal tissue into the renal subcapsular is evaluated in chapter 4, demonstrating that isografts survive indefinitely whereas allografts are rejected typically by 30 days. Pretransplant sensitisation decreased allograft survival time to 10 days. Immunohistochemistry demonstrated the presence of CD4+ and CD8+ lymphocytes and macrophages at the rejection site. Heterotopic corneal graft recipients were then treated with various monoclonal antibody regimes. Chapter 5 demonstrates that allograft survival can be increased by either anti-CD4 or anti-CD8 therapy, providing near total depletion of the respective lymphocyte subset is achieved. Xenograft rejection is shown to depend on mainly CD4+ lymphocytes in chapter 6, with no benefit being found of depleting the CD8+ subset in addition. A mild immunosuppressive effect of anti-Vβ8 monoclonal antibody is demonstrated and discussed in chapter 7. The final chapter discusses these results in the light of recent, related work in other transplant systems, and presents a case for a trial of intracameral pan-T-cell monoclonal antibody treatment.
7
Chain, Robert Whatley. "THE ROLE OF DENDRITIC CELLS IN GRAFT REJECTION." Master's thesis, Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/194726.
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Microbiology and ImmunologyM.S.
Induction of acquired immunological tolerance is the ultimate goal in transplantation. So far the acceptance of a mismatched graft is achieved through immunosuppression that requires long-term treatment and a variety of methods have been explored to prevent rejection and achieve transplant tolerance in mouse models. There are several factors that contribute to acquired tolerance. Recent studies have focused on the inhibition of costimulatory molecules and TLRs in Dendritic Cells (DCs), as a key to the mechanisms underlying the barrier to tolerance induction. Dendritic cells are the sentinels of the immune system. Immature Dendritic cells, which are characterized by low MHC Class II expression and weak T cell stimulation ability, reside in all organs of the body sampling the environment for antigens to bring back to the lymph nodes for T and B cell tolerization or activation, depending on the presence of danger signals. One of these danger signals is LPS from gram-negative Bacteria that can induce DC maturation by triggering TLR4, a surface PRR that is also stimulated by endogenous danger signals, like HMGB1, released during inflammation and tissue damage. Mature DCs highly express MHC II and costimulatory molecules and are potent T cell stimulators. However, LPS has multiple effects on DCs. Indeed, unpublished results from our lab also show that LPS induces DC cell death in vitro and in vivo. It has also been reported that DCs treated with LPS during their development remained in an immature state and they induced alloantigen-specific anergy of CD4+ T cells in vitro. The effects of the simultaneous exposure of DCs to LPS and endogenous danger signals requires further investigation. Therefore, we developed a mouse skin transplant model to determine the effects of LPS and endogenous danger signals, released during engraftment, on DC functions and the ability to induce rejection vs tolerance in transplantation. We used the spontaneous model of skin rejection of a single minor histocompatibility mismatch, the male-specific H-Y antigen. We performed skin grafts from the tail or ear of female or male C57BL/6 mice onto syngeneic female recipients. We administered 4 treatments of PBS 0.5ml or LPS 0.5ml at 25ug/mouse every other day starting from day 0. We observed that control mice transplanted with male skin completely rejected the graft between 24-34 days, while mice transplanted with male skin and treated with LPS did not show rejection of the graft until an average of 64 days and 50% of did not rejected at all. When we administered a different DC stimulator, the TLR9 ligand CpG, we found on the contrary that it induced acceleration of the graft rejection. To understand the mechanism underlying these results, we studied the DCs in vivo. Upon organ transplantation, DCs migrate out of the graft in the first 3 days. Studying the phenotype of the DCs migrating out of the skin graft, we found a sharp decrease of DCs in the skin graft as early as 48 hours post transplant and the loss of DCs was more severe with treatments of LPS. The analysis of the DCs in the epidermal sheets of the graft showed that mice treated with LPS treatment had strongly decreased numbers of DCs compared to mice injected with either PBS or with CpGs. Moreover, we analyzed the DCs from the graft-draining Lymph Nodes (Brachial and Inguinal), and from Spleen. We found again decreased numbers of DCs in both the Spleens and Lymph Nodes of grafted mice treated with LPS compared to mice injected with either PBS or CpGs. Based on these findings, we hypothesize that one of the mechanisms in which LPS prolongs graft survival is that it decreases the number of DCs leaving the graft to stimulate the immune response. LPS is either killing the DCs or holding them outside of the Lymph Nodes, not allowing for antigen presentation during the first week after transplantation when most of the DAMPS from the surgery and ischemia are released.
Temple University--Theses
8
Choi, Chi-wai, and 蔡志維. "Detection of class I-related polypeptide-related sequence A (MICA) and angiotensin II type 1 receptor (AT1R) antibodies in antibody mediated rejection in Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206596.
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Background: Rejection is considered as a major barrier to achieve successful transplantation. Non self-human leucocyte antigen (HLA) is a well-known antigenic target for antibodies binding that can result in antibody-mediated rejection (AMR). To reduce risk of rejection in kidney transplant, preventive measures are undertaken, which include HLA-matching between donor and recipient, and in-vitro pre-transplant crossmatch with potential donor cells and recipient sera, furthermore, periodic HLA antibodies monitoring for donor-specific antibodies (DSA) is carried out before and after transplant. Nevertheless, allograft may still fail despite the above measures, which suggests other antigens besides HLA can also contribute to renal rejection. In fact, polymorphic major histocompatibility complex (MHC) class I–related chain A (MICA) antigens and Angiotensin II type 1 receptor (AT1R) antigens have been reported as likely targets in AMR. However, the effect of non-HLA antibodies such as anti-MICA and anti-AT1R antibodies in rejection are not fully defined. This implies there is an imminent need to elucidate the role of non-HLA antibodies in allograft AMR cases which are not mediated by HLA antibodies.
Aim: To retrospectively evaluate the occurrence of MICA and AT1R antibodies in 21 clinical AMR cases without detectable HLA antibodies or HLA antibodies that were not target against donor HLA.
Methods: Twenty-one cases with suspected non-HLA mediated post-transplant rejection were retrieved. Eplet analysis was utilized to confirm that the detectable HLA-DR antibodies in one of the samples were not cross-reactive towards a donor’s antigen. Sera from 21 non-AMR cases were used as controls. All sera were subjected to MICA antibody and AT1R antibody screening. Identified positive cases were further examined with their pre-transplant sera to assess whether the AT1R and/or MICA antibodies were already pre-formed before transplantation. The sensitization histories of transfusion, pregnancy and previous transplantation were recorded.
Results: Nine of twenty-one cases were detected with MICA and/or AT1R antibodies. 7 samples were detected with MICA antibodies while 3 samples were detected with AT1R antibodies. A sample was detected with both MICA and AT1R antibodies. Importantly, the presence of MICA/AT1R antibodies appeared to be strongly associated with rejection caused by non-HLA antigens (p=0.0007). All controlled cases were found to be negative for MICA and AT1R antibodies. Pre-transplant sera of the positive cases were further screened and pre-formed antibodies were detected in 3 of the positive MICA cases, and 1 of the positive AT1R cases. Since no AT1R and MICA genotyping of the donor was carried out previously, it was uncertain that the allograft rejection was induced by the donor specific pre-formed antibodies generated in the pre-transplant sensitization events. Nonetheless, AT1R and MICA antibodies appeared to be induced by the allograft in the remaining 5 cases.
Conclusion: Presence of MICA/AT1R antibodies appeared to be associated with the investigated AMR cases without detectable HLA antibodies. Some evidence suggested the production of these non-HLA antibodies could be induced by transfusion sensitization or allograft upon transplantation.published_or_final_version
Pathology
Master
Master of Medical Sciences
9
Toogood, Giles John. "Cytokines in small bowel transplantation : expression during graft rejection." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297078.
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Figueiredo, Francisco Carlos D'Amorim de. "Immunopathology of corneal graft rejection in a rat model." Thesis, University of Bristol, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296671.
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Endo, Kosuke. "Pretransplant replacement of donor liver grafts with recipient Kupffer cells attenuates liver graft rejection in rats." Kyoto University, 2015. http://hdl.handle.net/2433/199205.
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Larsen, Christian Peter. "The migration and function of dendritic leukocytes after transplantation." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.256294.
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Antoniou, Antony Nicodemus. "Stimulation of immune responses by mutated transgenic self-products." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262551.
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Saxton, Nina Elizabeth. "Anti-TNF-#alpha# treatment in the rat heterotropic cardiac allograft model." Thesis, Open University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321566.
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Wang, Wen-Hua 1965. "Cytokine gene expression and gene therapy in experimental corneal graft rejection." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38529.
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It has been proposed that CD4+ T cells and cell-mediated immunity play a central role in corneal allograft rejection. Two subsets of CD4+ T cells, Th1 and Th2 cells, are known to cross-regulate each other through their cytokine pattern and the immune response might be directed predominantly in one or the other direction. As such, it has been hypothesized here that predominant Th1 type immune response could lead to corneal allograft rejection, and that previous inflamed corneal beds (high-risk eyes) might augment the Th1 response and thus accelerate the graft rejection.Reverse transcription of mRNA followed by polymerase chain reaction amplification was used to determine the relative gene expression in ocular tissues (cornea and iris/ciliary body) obtained from syngeneic grafts, low- and high-risk allografts. Compared with the syngeneic grafts, mRNA analysis of the low- and high-risk allografts showed a significantly decreasing expression pattern for the Th3 cytokine TGF-beta2, an early peak followed by a decline in the Th2 cytokines IL-4 and IL-10 expression, and a progressively increasing expression of the Th1 cytokines IL-2 and IFN-gamma and the proinflammatory cytokines IL-1beta and TNF-alpha, which paralleled the course of graft rejection. Prevascularization of the recipient eye (high-risk) significantly accelerated the rejection of corneal allografts and the mRNA levels of the Th1 cytokines IL-2 and IFN-gamma and proinflammatory cytokines IL-1beta and TNF-alpha in high-risk allografts were significantly higher and peaked faster than that in low-risk allografts.
In vivo gene transfer using plasmid DNA encoding cytokines is an attractive alternative to modulate the Th1 inflammatory reaction and immune response. This has led to the hypothesis that transferring the gene encoding Th2 cytokine IL-10 into the recipient could prevent or reduce the subsequent corneal allograft rejection through the suppression of Th1-mediated alloimmune response.
Intramuscular injection with in vivo electroporation of IL-10 plasmid DNA was administered at one week before and at one week after corneal transplantation. Corneal allograft survival was significantly prolonged and the rejection rate was significantly reduced after gene therapy with IL-10 plasmid DNA, compared with that in control groups treated with the empty plasmid vector. In IL-10 treated rats, the mRNA expression for the Th1 cytokines IL-2 and IFN-gamma was depressed, and the IL-10 mRNA expression was significantly increased. However, graft survival was not permanent. (Abstract shortened by UMI.)
16
Loh, Yik Wen. "Analysis of CD4 T cell-dependent skin and islet graft rejection." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13085.
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Studies described in this thesis made use of the CD4+ 5C.C7 TCR transgenic model to analyse CD4+ T cell responses in two models of fully MHC-mismatched non-vascularised grafting: skin and islet grafts. The crossreactive specificities of the 5C.C7 TCR model allow the investigation of direct allorecognition and the role of heterologously primed memory cells in allogeneic graft rejection or acceptance. Data presented is consistent with a model in which memory, not naïve CD4+ T cells, primed by environmental exposure before the time of grafting and expressing allo-crossreactive specificities, are uniquely capable of initiating graft rejection by entering graft site directly from the bloodstream, attacking the graft and liberating MHC antigens from the graft so that they reach the circulation and can then interact with both naïve and memory cells in the secondary lymphoid tissues. This highlights the critical role of memory cells in initiating allograft rejection and has important implications for future development of tolerance strategies for clinical application. Additionally, work presented includes the establishment of a diabetogenic drug induced diabetes model for islet transplantation, as well as the novel application of intravital multiphoton system to image full thickness flank skin and islet grafts under the kidney capsule.
17
Hunt, James Barrie. "Endomyocardial biopsy diagnosis of acute cardiac allograft rejection." Master's thesis, University of Cape Town, 1991. http://hdl.handle.net/11427/25718.
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The aims of the present investigation are fourfold: (i) to review the range of non-invasive methods that may be used to diagnose acute cardiac allograft rejection; (ii) to review the use of the bioptome in sampling the donor heart endomyocardium; (iii) to review the light microscopic and histological grading of acute cardiac rejection; (iv) to characterise the mononuclear populations in endomyocardial biopsy samples and correlate the findings with the light microscopic appearances of the same biopsy specimens.
18
Otasevic-Wieschalla, Ljiljana [Verfasser]. "New drugs in prevention of experimental corneal graft rejection / Ljiljana Otasevic-Wieschalla." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1057870056/34.
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Robinson, Rebecca Hartzell. "Cannabinoid Receptor 2-Selective Ligands as Immunosuppressive Compounds: Utility in Graft Rejection." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/246094.
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Microbiology and ImmunologyPh.D.
Cannabinoids are known to have anti-inflammatory and immunomodulatory properties. Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes. The capacity of delta-9-tetrahydrocannabinol (delta-9-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation was tested. Both CB2-selective agonists and delta-9-THC significantly suppressed the MLR in a dose dependent fashion. The inhibition was via CB2, as suppression could be blocked by pretreatment with a CB2- selective antagonist, but not by a CB1 antagonist, and none of the compounds suppressed the MLR when splenocytes from CB2 deficient mice were used. The CB2 agonists were shown to act directly on T-cells, as exposure of CD3+ cells to these compounds completely inhibited their action in a reconstituted MLR and proliferation of purified T-cells by anti-CD3 and anti-CD28 antibodies was inhibited. Treatment of both CD4+ and CD8+ T-cells with a CB2-selective agonist inhibited the MLR, though significantly less than when both cell types were treated. T-cell function was decreased by CB2 agonists, as an ELISA of MLR culture supernatants revealed IL-2 release was significantly reduced in the cannabinoid treated cells. Further, treatment with O-1966 dose- dependently decreased levels of the active nuclear forms of the transcription factors NF- kappa-B and NFAT in wild-type T-cells, but not T-cells from CB2 knockout (CB2R k/o) mice. Additionally, a gene expression profile of purified T-cells from MLR cultures, generated using a PCR T-cell activation array, showed that O-1966 decreased mRNA expression of CD40 ligand and CyclinD3, and increased mRNA expression of Src-like-adaptor 2 (SLA2), Suppressor of Cytokine Signaling 5 (SOCS5), and IL-10. The increase in IL-10 was confirmed by measuring IL-10 protein levels in MLR culture supernatants. An increase in the percentage of regulatory T-cells (Tregs) was observed in MLR cultures and pretreatment with anti-IL-10 resulted in a partial reversal of the inhibition of proliferation and blocked the increase of Tregs. Additionally, O-1966 treatment caused a dose-dependent decrease in the expression of CD4 in MLR cultures from wild-type, but not CB2R k/o, mice. The ability of O-1966 treatment to block rejection of skin grafts in vivo was also tested. Mice received skin grafts from a histoincompatible donor, and the time to graft rejection was analyzed. Compared to mice that received the vehicle, mice that received O-1966 treatment had significantly prolonged graft survival and increased Tregs in the spleen. The spleen cells from O-1966-treated mice had reduced proliferation in an MLR and an increased percentage of Tregs. Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients and possibly as a new class of immunosuppressive drugs.
Temple University--Theses
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Ballow, Amany A. "The implications of different IgG subclasses on graft rejection in sensitized individuals." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6182.
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The presence of memory B cells may contribute to graft damage. In fact, pre-transplant B cell sensitization in the absence of circulating antibody represents a risk factor, since grafts transplanted into recipients with historical positive but current negative direct crossmatch do less well than patients with no evidence of B cell sensitisation. This definition of ‘negative’ is based on conventional complement-dependent cytotoxicity (CDC) assays and, more recently, on flow cytometry. In this study, I have analysed the significance of antibodies undetectable by these conventional techniques but found to be present using the more sensitive novel Luminex technology which has now become available to detect class I and class II HLA-specific antibodies present in pre-transplant patients’ sera at the time of transplantation. Even in the absence of low level antibodies, there may still be undetected B cell sensitization. An ELISpot assay has previously been developed to quantitate B cell responses. In this study, I have developed the ELISpot assay in an attempt to determine B cell allosensitization. This project aims were: 1. To evaluate the relationship between renal transplant outcome and the presence of low grade HLA-specific IgG-antibodies pre-transplant, both non-donor-specific as well as donor-specific antibodies detected using Luminex technology. 2. To develop ELISpot assays that detect the potential responses of the various cells of the B cell compartment, reflecting naive allo-reactivity as well as that which has been induced by historical sensitisation events. 3. To detect the presence of post-transplant HLA-specific IgG antibodies (both donorspecific and non-donor specific) in tolerant drug-free patient and determine their significance in defining the state of tolerance. Summary of the results: 1. Luminex technology is a more sensitive technique than flow cytometry and CDC in detecting low-level donor-HLA-specific antibodies which were present in pre-transplant patients’ sera at the time of transplantation and is associated with a higher incidence of rejection episodes. 2. IgM- and IgG-detecting ELISpot assays were developed to determine the frequency of antibody-secreting cells. I have begun to apply these methods to determine the humoral reactivity against alloantigen in sensitised patients. 3. Tolerant drug-free patients had no detectable donor-specific antibodies (DSA). In the non-tolerant patients, DSA-positive patients had worse graft function than DSAnegative patients.
21
Wennberg, Lars. "Islet xenograft rejection : studies in the pig-to-rodents and pig-to-primate models /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2835-5.
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Niimi, Masanori. "An investigation to determine the ability of allogeneic resting B cells to induce specific unresponsiveness in vivo." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244813.
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Lovegrove, Emma. "Indirect T cell allorecognition of the RT1.A'a MHC class I molecule." Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340253.
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Coxon, Fraser P. "Properties of cyclophilins and their ligands in bone." Thesis, University of Sheffield, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263761.
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Sharma, Ankit. "The impact of eplet mismatches and de novo donor specific antibodies in kidney and simultaneous pancreas-kidney transplantation." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/24228.
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Improving kidney transplant graft survival is of critical importance to patients, caregivers and health professionals. Advances in immunosuppression regimens have mitigated the risk and injurious effects of T-cell mediated rejection resulting in increased graft survival rates, particularly in the first year after transplantation. The leading cause of graft attrition is now antibody mediated rejection (AMR), implicated in up to two thirds of graft loss after one year. Donor specific antibodies (DSA) are central to the pathogenesis of AMR, with the presence of pre-transplant DSA (or sensitisation) reducing access to transplantation due to the risk of hyper-acute or acute AMR. Children with end-stage kidney disease (ESKD) are particularly disadvantaged by sensitisation due to their expected need for re-transplantation, yet strategies to avoid sensitisation and overcome this antibody barrier are poorly defined. Chapter 2 of this thesis provides an overview of sensitisation and desensitisation therapies in children with ESKD.
Similar to pre-transplant DSA, de novo DSA (dnDSA) may form after transplantation and are implicated in AMR. The incidence and magnitude of effects of dnDSA on graft and patient outcomes is however variably reported in the literature. Chapter 3 of this thesis provides a systematic review and meta-analysis of the association between dnDSA and graft and patient outcomes.
Greater understanding of the harmful effects of dnDSA has increased interest in developing strategies to avoid their development. Current assessment of histocompatibility considers whole HLA antigen mismatches, the precision of which may be improved by accounting for differences in the surface antibody accessible amino acid sequences (eplets) on donor and recipient HLA. Previous studies have demonstrated that increasing number of eplet mismatches are associated with dnDSA development, acute rejection and transplant glomerulopathy. This relationship is particularly evident for HLA class II eplet mismatches and is modified by immunosuppression. The longitudinal relationship between eplet mismatches, dnDSA and acute rejection outcomes has however been poorly defined in children and is addressed by Chapter 4 of this thesis.
Apart from requiring a greater understanding of the causal pathways between eplet mismatches and graft outcomes, a further challenge to utilising eplet mismatch information in organ allocation is the large number and complexity of mismatches which require consideration. Eplet mismatches are recognised to have innate properties such as electrostatic potential which confer their ability to induce an immune response (immunogenicity) or produce subsequent alloantibody recognition (antigenicity). Differentiating between the specific eplet mismatches which are predictive of adverse graft outcomes and those which are less likely to produce an immune response may allow assignment of unacceptable mismatches and permissible mismatches, thus simplifying implementation into organ allocation. Chapters 5 and 6 of this thesis identify specific eplet mismatches which predict dnDSA and acute rejection outcomes.
The studies within this thesis collectively detail the relationship between eplet mismatches, dnDSA and acute rejection in kidney transplantation and identify specific eplet mismatches which are predictive of adverse graft outcomes.
26
Wang, Chuanmin. "Studies of allograft tolerance in rodents." Thesis, The University of Sydney, 2000. https://hdl.handle.net/2123/27722.
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Allograft rejection is still the main obstacle to successful treatment of
patients with end—stage organ failure by organ transplantation. Both tolerance
and rejection of allografts are complicated responses of the host immune
system to foreign antigens. It is almost 50 years since Billingham, Brent, and
Medawar first described the phenomenon of neonatal tolerance to skin
allografts in a murine model. Tolerance to vascularised organ allografts was
subsequently described in pig, rodent, and primate models. Knowledge
regarding the mechanisms by which tolerance is induced and maintained has
increased dramatically over recent years, but the ultimate understanding of the
mechanism of allograft tolerance remains elusive. The aim of this thesis, based
on rodent organ transplant models, is towards a better understanding of the
mechanism of allograft tolerance induction and maintenance.
The first part of the allograft tolerance study in rats is described in
chapter 4. Here, liver transplants’protect subsequent pancreatic grafts from the
same donor strain from rejection and also reverse ongoing pancreas graft
rejection, with subsequent pancreas acceptance. In this study, liver transplants
from PVG (RT1 ) to DA (RT1a) strains were accepted spontaneously with a
median survival time (MST) greater than 120 days without evidence of graft
rejection, while pancreas grafts in the same strain combination were rejected
promptly with MST of 9 days. Liver transplantation followed by pancreas
transplantation at 4 weeks resulted in protection of all pancreas grafts from
rejection with survival greater than 120 days in all except two animals which
died of liver graft rejection on days 56 and 67 with normal pancreas graft
function. Pancreas transplantation followed by liver transplantation on days 2, 4,
and 6 showed that the liver grafts reverse ongoing pancreas graft rejection, with
subsequent pancreas acceptance in all transplants at the 2- and 4-day intervals
and in 3 out of 5 transplants at the 6-day interval. In the group where pancreas
transplant was followed by liver transplant on day 4 two animals died of liver
graft rejection on days 75 and 84 and one animal died of liver graft rejection on
day 20 in the group where pancreas transplant was followed by liver transplant
on day 6; in all animals dying with liver rejection the pancreas graft function
remained intact. These two experiments suggest that either prior or subsequent
stimulus by donor antigens is capable of triggering a rejection response against
an otherwise spontaneously accepted liver graft — a stimulus that is not
effective when applied concurrently with the liver graft.
27
Cai, Qi, and 蔡綺. "The possible mechanisms of peroxisome proliferator-activatedreceptor (PPAR) agonists in controlling graft rejection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36396199.
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Wilson, Nicole K. "Borderline Lesions Exhibit Clinical and Graft Survival Characteristics Common to Acute Cellular Rejection." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627665576477761.
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Wong, Jeffrey K. W. "Chemokines and chemokine receptors in islet xenograft rejection." Thesis, The University of Sydney, 2006. https://hdl.handle.net/2123/28055.
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This project investigates the role of chemokine and chemokine receptors in a model
of CD4 T cell dependent cellular xenograft rejection, specifically the transplantation
of fetal pig pancreas tissue to the renal subcapsular space of mice.
Chemokines and chemokine receptor gene expression was assessed by cDNA arrays,
and confirmed by multi-probe ribonuclease protection assay. Immunostaining for a
selected chemokine, RANTES was performed to demonstrate upregulation at the
protein level.
These methods were applied to several different models to dissect the role
Chemokines and their receptors in this process. Comparisons were made with: an
allografi model, a model where indefinite xenograft survival could be achieved by
short term costimulatory blockade with CTLA4-Fc and MR1, and an
immunodeficient mouse recipient (RAG—1 KO, lacks B and T cells) that was
reconstituted with either unfractionated leucocytes or purified CD4 T cells.
The main findings were:
1. Allograft rejection and cellular xenografi rejection are THl type CD4 T cell
dependent processes as shown by the common T cell chemokine genes (Ltn,
IP-lO, and Mig) expressed in both models; however macrophages are the
main effector cell in cellular xenografi rejection as evidenced by the selective
upregulation of MCP-l and its receptor CCR2, as well as other macrophage
markers
2. Of the Chemokines / receptors upregulated in this model of cellular xenograft
rejection (Ltn, IP-lO, MCP-l, RANTES, MIP-lB, eotaxin) only MCP-l and
IP-lO are CD4 T cell dependent, while Ltn expression is dependent upon a
non-CD4 T cell leucocyte subset.
3. CTLA4-Fc and MR1 therapy resulted in indefinite fetal porcine islet survival
and function in diabetic immune competent wild type C57BL/6 mice. This
treatment suppresses the early upregulation of chemokines and chemokine
receptors seen in untreated animals, and this corresponds with a significant
reduction CD4 T cell and macrophage grafi infiltration at these time points,
consistent with a role for select chemokine / receptors in the mechanism by
which this therapy leads to indefinite graft survival.
4. In addition we studied the functioning of fetal porcine islet tissue in diabetic
mice and found they developed and controlled glucose metabolism in a piglike
manner, and different to normal mice, and thus conclude the development
and function of fetal tissue in cross species transplantation is dependent upon
the origins of the progenitor cells and not the xenogeneic environment i.e.
nature not nurture (in this case anyway).
We conclude that select chemokines and their receptors are important factors in the
recruitment of effector cells mediating graft rejection in this model of cellular
xenograft rejection and these chemokine pathways and networks may represent
potential future therapeutic targets.
30
Chinaelli, Marco. "99mTc labelling of interleukin-2 for in-vivo detection of lymphocytic infiltration." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243365.
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Reel, Michael Stephen. "The Role of Ectopic Lymphoid Tissue in Allograft Rejection." Yale University, 2006. http://ymtdl.med.yale.edu/theses/available/etd-06282006-140255/.
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The location of the immunologic response to an allograft is not known with certainty. However, organized collections of T cells, B cells and antigen presenting cells have been found in peripheral tissue, in close proximity to organs undergoing rejection. It is hypothesized that this tertiary lymphoid tissue may be a location in which activation of lymphocytes can occur, leading to rejection of an allograft. We report here that in a splenectomized aly/aly mouse, which is devoid of secondary lymphoid organs and will normally fail to reject an allograft, the presence of tertiary lymphoid organs is associated with graft rejection. We additionally find that tertiary lymphoid organs can act as lymph nodes, and can support effector and memory allograft rejection responses. It is demonstrated that ectopic lymphoid tissue in aly/aly mice will support the multiplication and transformation of transferred naïve CD4 and CD8 T cells into cells that display phenotypic markers characteristic of effector and memory lymphocytes. These results demonstrate that ectopic lymphoid tissue is associated with the loss of immunologic ignorance and is sufficient to enable graft rejection. This suggests that allograft rejection may take place within ectopic lymphoid tissue, and suggests that techniques to interfere with the development of this tissue might offer a therapeutic approach to preserving organ allografts.
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McLean, Adam George. "Patterns of graft infiltration and cytokine gene expression during the first ten days of kidney transplantation." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390513.
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Cai, Qi. "The possible mechanisms of peroxisome proliferator-activated receptor (PPAR) agonists in controlling graft rejection." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B36396199.
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Ge, Xupeng. "Mechanisms of liver allograft rejections /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-330-2/.
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Scully, Ralph. "Mechanisms in transplantation tolerance." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321084.
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Khosravi, Maharlooei Mohsen. "Deploying the tolerogenic effects of IDO enzyme and skin fibroblasts in prevention of graft rejection." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62706.
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Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme with tolerogenic effects on different immune cells. Our group has previously shown that co-transplantation of IDO-expressing fibroblasts with donor tissues can delay immune rejection by inducing local immunosuppression. We first asked a question whether we can improve this effect by delivering the IDO-fibroblasts through a systemic intraperitoneal approach, instead of local co-transplantation, and secondly whether this effect is only delivered by the immunosuppressive effects of IDO or the fibroblast cells have additional immunosuppressive effects.
We employed a systemic approach to improve allograft survival without using any immunosuppressive medication. To achieve this, 10 million lentiviral transduced IDO-expressing donor derived fibroblasts were injected into the peritoneal cavity of allograft recipients. We showed that IDO-fibroblast therapy increases the survival of both islets and skin allografts and decreases the infiltration of immune cells in subcutaneous transplanted skins. Indirect pathway of allo-reactive T cell activation was suppressed more than the direct pathway. Injected IDO-fibroblasts were found in peritoneal cavity and mesenteric lymph nodes of the recipient mice. In conclusion, fibroblasts have tolerogenic effects on DCs and IDO-expressing fibroblast therapy proved to be a novel approach in improving the allogeneic graft survival.
There is controversy about the immunomodulatory effect of fibroblasts on dendritic cells (DCs). In a mouse model, we showed that intra- peritoneal injection (IP) of both syngeneic and allogeneic fibroblasts significantly increased the expression level of co-inhibitory and co-stimulatory molecules on DCs. Priming of DCs with syngeneic and allogeneic fibroblasts reduced the proliferation of CD4+ and CD8+ T cells. Even activation of fibroblast-primed DCs failed to restore their ability to induce T-cell proliferation. Likewise, priming of DCs with fibroblasts blocked the ability of ovalbumin-pulsed DCs to induce proliferation of ovalbumin-specific CD4+ T cells. Compared with non-activated DCs, fibroblast-primed DCs had significantly higher expression levels of interleukin-10 and IDO. Fibroblast-primed DCs had a significantly reduced interleukin- 12 expression level compared with that of activated DCs. After priming with fibroblasts, DCs were able to migrate to lymphatic tissues and present fibroblast-derived antigens (ovalbumin).Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Li, Daxu, and 李大旭. "Role of adiponectin in preventing chronic rejection and the underlyingmolecular immunoregulatory signaling pathway." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47155966.
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Chronic rejection is a major obstacle to long-term survival of organ transplants. PPAR-γ agonist rosiglitazone has been shown to reduce graft rejection but the underlying mechanisms remain unclear. Combined treatment of rosiglitazone and anti-IL-5 antibody prevented MHC class II histoincompatiblecardiac graft rejection with a reduction of cellular infiltration, vasculopathy and interstitial fibrosis in a heterotopic heart transplantation model. In particularly, rosiglitazone decreased CD8 T cells infiltration and luminal occlusion, while anti-IL-5 antibody reduced eosinophil infiltration and collagen deposition. Adiponectin gene (APN) is a PPAR-γ target gene, and the expression of APN receptor AdipoRII in grafts, dendritic cells (DCs) and T cells are increased by rosiglitazone. These findings prompted me to further examine the immunomodulatory role of APN in graft rejection.
APN is an anti-inflammatory adipocytokine, and has been shown to inhibitimmunostimulatory function of monocytes and macrophages. Rosiglitazone suppresses DCs maturation, activation and proliferation;hence, it is possible that APN could protect graft rejection through immunoregulation of DCs. Here, using in vitro culture systems, I found that APN has only moderate effect on the differentiation of bone marrow derived DCs but itcould alter DC phenotypes. APN-treated DCs showed an increased expression of PD-L1, which is consistent with the increased PD-L1 expression in rosiglitazone treated cardiac allografts. APN-treated DCs led to a decreased proliferation and reduction of IL-2production of T cell. Moreover, APN-treated DCs increased the expansion of Tregs (regulatory T cells) which could be inhibited by the blockage of PD-1/PD-L1 pathway, suggesting that PD-1/PD-L1 pathway and expansion of Tregs played important roles in APN-treated DCs mediated immunomodulation.
Further, I employed APN-/-mice for functional and mechanistic studies, and found that cardiac allografts were not rejected by APN-/-recipient mice even after 120 days post-transplantation. Histological analyses revealed very little eosinophils, CD4 and CD8 T cells infiltration; no collagen deposit and no vessel occlusion in the cardiac allografts. Furthermore, Th2 cytokines such as IL-4 and IL-5 were lower in cardiac allografts and in the serum of APN-/-recipient. Inhibition of AMPK signaling, a major APN mediated pathway, reduced the eosinophils infiltration in wild type recipient. In contrast, AMPK activation increased eosinophils infiltration in APN-null recipient.
APN enhanced T cell proliferation. AMPK and P38MAPK inhibitors as well as anti-IL-4 antibody inhibited APN-induced T cell proliferation. P38 MAPK inhibitors reduced IL-4 production in mature DCs but enhanced IL-4 expression in immature DCs. In EL-4 T cells, APN increased nuclear expressions of GATA-3 and p-STAT6 and augmented IL-4 expression, and the phenomenon was suppressed by target specific knockdown of AdipoR I and II.
In summary, current study provides new mechanistic insights of PPAR-γ activation and APN signaling in the modulation of adaptive and transplantation immunity, establishing a link between metabolism and immune regulation.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy
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Stone, John. "Assessing the impact of ex vivo perfusion on graft immunogenicity." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/assessing-the-impact-of-ex-vivo-perfusion-on-graft-immunogenicity(a8ad264a-8925-44ee-94c0-465d3ddd7e14).html.
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Whilst the major caveat to the success of organ transplantation remains the severe lack of donor organs, rejection is still a primary confounding factor to transplant outcomes. This is an allospecific response that occurs when the recipient immune system recognises conserved proteins on donor-derived cells as 'non-self'. Currently, all immunosuppressive regimes target the recipient immune response, ignoring the large donor immune repertoire despite these cells playing a central role in acute rejection. This is likely as a result of a lack of understanding of the temporal migration of the donor compartment and its contribution to the inflammatory cascade that ensues. The development of ex vivo perfusion provides the opportunity to assess this in isolation, with no confounding factors. Furthermore, inducing the mobilisation of passenger leukocytes on an ex vivo circuit allows their removal prior to transplantation. Reducing the inflammatory burden of donor organs has the potential to impact on the clinical outcome of patients, manifesting as a reduction in the incidence or severity of acute rejection. The aim of this PhD thesis was to characterise the donor immune compartment of lungs and kidneys, to assess the impact of ex vivo perfusion on this, and determine the post-transplant impact of removing a proportion of these cells. For this purpose, donor lungs were perfused using ex vivo lung perfusion (EVLP) and the immune compartment characterised. A comparison of EVLP versus standard transplanted lungs was performed using a porcine transplant model. Clinical parameters were recorded and a histological assessment of cellular infiltration was performed to diagnose the incidence of acute rejection. To determine if these results were translatable to other organs, a porcine model of kidney ex vivo perfusion was established. In both models, a significant efflux of donor leukocytes was observed and inflammatory mediators detected. In a transplant model of EVLP, reducing the transfer of these passenger leukocytes translated into improved clinical outcomes, manifesting as a lower incidence of acute rejection, for animals receiving EVLP lungs compared to a standard transplant. Similar benefit is likely to occur following transplantation of perfused kidneys. This study describes for the first time the contribution of donor organs to the inflammatory processes that ensue following transplantation. It is clear that this untargeted population is of significant importance in clinical outcomes. Immunomodulatory strategies to alter the donor immune environment prior to transplantation therefore warrant development.
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Ehrnfelt, Cecilia. "In vitro models of xenograft rejection : studies on leukocyte-endothelial cell interactions /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-807-6/.
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Kassis, Elias Noah. "Nanoparticle use in the modulation of transplant rejection in a murine model." Yale University, 2010. http://ymtdl.med.yale.edu/theses/available/etd-03052010-124710/.
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Solid organ transplant has emerged over the last half century as an important treatment for solid organ failure. Management has matured dramatically over the past two decades with improvements in acute rejection, but long-term graft survival has improved very little and current treatment is limited by the side-effects and toxicities of immunosuppressive medications. Nanoparticle delivery of therapeutics, improving transport characteristics and decreasing systemic and local toxicity has emerged as a dynamic treatment modality, but little work has been done using nanoparticles in transplantation. Our research examined the use of CD4-targeted nanoparticles encapsulated with mycophenolic acid (MPA), a commonly used immunosuppressant in organ transplantation. This work is the first to examine antigen-specific targeting of nanoparticles in any transplant model. MPA-loaded particles show a slow and continuous release profile and biodistribution suggested retention in the spleen. Targeting of nanoparticles to CD4 T cells was suggested using ex vivo and in vitro flow cytometry. In the fully allogeneic MHCII mismatch BALB/C to C57BL/6 mice we found improved graft survival in the non-targeted MPA group and even greater graft survival in the CD4-targeted group. Targeted and non-targeted particle groups showed equal delay in rejection in the less immunogenic single MHC mismatch B6.H-2bm12 to C57BL/6 model that we showed to be CD4 dependent. In both models, graft survival times were increased over free drug and controls with roughly one thousand fold lower dose of drug in the nanoparticles as compared with free MPA. Consistent with these findings were decreased proliferation with targeted and non-targeted MPA-nanoparticles using in vitro and ex vivo mixed lymphocyte reactions. We postulated that the similar rejection times in targeted and non-targeted groups was due to dendritic cell (DC) involvement and we found active uptake of nanoparticles in DCs, a decrease in inflammatory cytokine production and a decrease in treated DCs ability to stimulate T cells via mixed lymphocyte reactions. Furthermore we found a possible mechanism in the DC interaction with T cells through the upregulation of the inhibiting co-stimulatory molecules B7-DC and B7-H1 on DCs treated with MPA-nanoparticles. We also found possible upregulation of CD4+CD25+ Foxp3 expressing Tregs which may serve to increase graft acceptance. These results explore the involvement of dendritic cells in the process of nanoparticle-induced graft acceptance and suggest the feasibility of using nanoparticle drug vectors in clinical transplant.
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Adeegbe, Dennis O. "Allogeneic CD4+CD25+Foxp3+ T Regulatory Cells in Autoimmunity and Transplantation Tolerance: Therapeutic Potential and TCR Repertoire Requirement." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/43.
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CD4+CD25+Foxp3+ T regulatory (Treg) cells are critical in maintaining self tolerance and promoting the acceptance of allogeneic tissue/organ grafts. To be widely applied in clinical settings, there needs to be a readily available source of Treg cells, a requirement that is better met if non-histocompatible donor cells could be utilized in adoptive therapy. Therefore, to investigate the therapeutic potential of fully allogeneic Treg cells to control autoimmune disease or allograft rejection, we utilized IL-2R beta-deficient mice that exhibit rapid lethal autoimmunity due to low production of an ineffective population of Treg cells. We show that adoptive transfer of MHC-mismatched Treg cells into IL-2R beta-/- mice resulted in life-long engraftment of the donor cells, which exhibited skewed reactivity toward host alloantigens, and prevented autoimmunity. When such animals received skin grafts, they exhibited tolerance to those grafts that expressed MHC molecules from which the donor Treg cells were derived. Collectively, these data provide proof-of-principle that effective engraftment by allogeneic Treg cells controls autoimmunity and leads to favorable conditions for long-term acceptance of allografts. Current data indicates that CD4+CD25+Foxp3+ Treg cells exhibit a broad TCR repertoire. However, the relationship between this diversity and capacity to control a similarly diverse population of potentially autoreactive T cells remains to be defined. To investigate this issue, we assessed the TCR repertoire of chimeric donor Treg cells in IL-2R beta-/- mice that were adoptively treated with a diverse polyclonal Treg inoculums. We demonstrate that autoimmune disease was fully prevented by engrafted donor Treg cells in spite of a TCR repertoire that is less diverse than the input cells. However, in settings where the input TCR repertoire is limited by utilizing donor Treg cells that express a single TCR beta chain, control of disease was hampered, correlating with a limited TCR alpha repertoire within the engrafting donor Treg cells. Collectively, these findings suggest that for adoptive therapy, a diverse TCR repertoire of input Treg cell inoculums is an essential requirement for effective control of polyclonal autoreactive T cells but perturbations in the repertoire that results in significant limitation to this diversity may compromise Treg cell efficacy at fully keeping autoaggressive cells in check.
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Lui, Sing-leung, and 雷聲亮. "The in vivo mechanism of actions of mycophenolate mofetil: insights from murine models of allograft rejection,endotoxemia, ischemia reperfusion injury and lupus nephritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B26625374.
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Lai, Sum Wing Christina. "An Analysis of Strategies Targeting Early Clinical and Immunological Events to Improve Kidney Transplant Outcomes." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29651.
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Background: Kidney transplantation is an essential treatment for patients with end-stage renal failure. The long-term fate of the transplant often depends on early events, including the development of delayed graft function (DGF) and rejection. However, there are barriers to targeting these risk factors to improve outcomes. First, DGF is associated with an increased incidence of acute rejection, but there is a lack of consensus around how to diagnose DGF. Second, despite growing recognition of the role of inflammatory monocytes (MΦ) in rejection, no clinically available treatment specifically targets MΦ. Previous work of our group has shown the efficacy of an immune-modifying nanoparticle (IMP) in preventing ischaemia-reperfusion injury; however, the role of IMP in rejection is unknown. This thesis, therefore, aims to evaluate potential strategies targeting early clinical and immunological events to improve transplant outcomes.
Methods: A systematic review of all adult and paediatric clinical trials on diagnostic tests for DGF is presented in Chapter 4. All clinical studies evaluating novel methods performed post-transplant to diagnose DGF in both living and deceased donor kidney transplantation recipients were identified through a comprehensive search strategy. The risk of bias for each study was assessed using the quality assessment of studies-2 tool. A fully major histocompatibility complex (MHC)-mismatched kidney transplantation model was used to evaluate the therapeutic potential of IMP in transplantation. The role of IMP in attenuating acute rejection was first explored in Chapter 5, where mice were sacrificed on day 14 post-transplant. The long-term effects of IMP on kidney survival and allograft function were further evaluated in Chapter 6.
Results: Thirty-seven studies were included in the systematic review, including 1916 kidney transplant recipients. There was marked heterogeneity among studies, and the reporting quality was generally low. Among the 20 biomarkers studied, the most frequently evaluated were serum neutrophil gelatinase-associated lipocalin (NGAL) (8 studies; 357 participants), urine NGAL (7 studies; 387 participants), and serum cystatin C (4 studies; 297 participants). No superior biomarker was found, but serum NGAL has the greatest potential as an objective diagnostic test.
In the mouse model of transplantation, mice treated with IMP, compared to those without, exhibited superior survival with less acute rejection at day 14. IMP prevented the infiltration of MΦ in the allograft and diverted them to the spleen. At day 100 post-transplantation, treated mice exhibited reduced macrophage responses but were not protected from chronic rejection.
Conclusions: This thesis provides further insight into the diagnostic tests for DGF and the nanoparticle-based treatment for rejection. Although the systematic review has not identified a superior biomarker, we have identified that serum NGAL has the greatest potential as a diagnostic test. Further assessment and validation are essential through larger-scale studies. By targeting MΦ, IMP improved allograft survival and prevented acute allograft rejection, proving its therapeutic role as an induction agent in transplantation.
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Sleater, Michelle Leigh. "Cellular and molecular effector mechanisms of islet allograft rejection /." Connect to full text via ProQuest. IP filtered, 2006.
Find full textAbstract:
Thesis (Ph.D. in Immunology) -- University of Colorado at Denver and Health Sciences Center, 2006.Typescript. Includes bibliographical references (leaves 151-168). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Reichenspurner, Hermann. "An assessment of a new immunosuppressive agent 15-deoxyspergualin (15-DS) following cardiac and renal allotransplantation and cardiac xenotransplantation in primates / does 15-deoxyspergualin induce graft nonreactivity." Doctoral thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/26253.
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Cena, Tiziana. "Post-kidney transplant malignancies affect graft survival: results from a time-dependent analysis." Doctoral thesis, Università del Piemonte Orientale, 2018. http://hdl.handle.net/11579/105206.
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Aim of this study was to evaluate the association between cancer occurrence and risk of graft failure in kidney transplant recipients. From 1998 to 2013, 672 adults receiving their first kidney transplant from a deceased donor, with at least six months of follow-up, were included in the study. To illustrate the effect of tumors incidence on graft failure risk, a modified Kaplan-Meier method was used. To quantify the tumor effect as hazard ratio, multivariable adjusted Cox models were fitted considering the diagnosis of non-cutaneous malignancies (NCM) and non-melanoma skin cancer (NMSC) as a time-dependent covariates.
The 5-year cumulative incidence of graft failure was 7.5% (95%CI: 5.3-10.0), with 59 events (39 due to chronic rejection and 20 for other causes). Forty patients developed a NCM (5-yrs cumulative incidence: 5.6%), and 47 developed a NMSC (5-yrs cumulative incidence: 6.5%). From the multivariable Cox model, the adjusted hazard ratio of graft failure associated with NCM was 3.27 (95%CI=1.44-7.44, p=0.005). The occurrence of a NMSC was not associated with graft failure (HR = 0.80; 95% CI = 0.30-2.14, p = 0.66). The model validation procedure (a leave-one out cross validation) showed a C-statistics of 0.80 (95%CI: 0.72-0.88) for the cross-validated cohort, ruling out model overfitting and validating its predictive ability. Investigating the effects of NCM on cause-specific graft failure, an NCM diagnosis seemed to have a different association (P = 0.002) when considering graft failed due to chronic rejection (HR 0.55, 95% CI: 0.07-4.08) or for other causes (HR 15.59, 95% CI 5.43-44.76). The reduction of the immunosuppression after NCM was not associated with a greater risk of graft failure. In conclusion, our data suggest that post-transplant NCM may be a strong risk factor for graft failure, particularly for causes other than chronic rejection, and more efforts should be addressed to improve graft outcomes acting on malignancy-associated nephropathies.
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Zhao, Xiangli [Verfasser]. "Investigation on the role of CD26 in Th1 and Th17 cell differentiation and allogeneic graft rejection / Xiangli Zhao." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1158597665/34.
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Forman, Daron. "Viral Abrogation of Stem Cell Transplantation Tolerance Causes Graft Rejection and Host Death by Different Mechanisms: A Dissertation." eScholarship@UMMS, 2002. https://escholarship.umassmed.edu/gsbs_diss/72.
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Tolerance-based stem cell transplantation using sub-lethal conditioning is being considered for the treatment of human disease, but safety and efficacy remain to be established. In order to study these two issues, we first established that mouse bone marrow recipients treated with sub-lethal irradiation plus transient blockade of the CD40-CD154 costimulatory pathway develop permanent hematopoietic chimerism across allogeneic barriers. Our conditioning regimen of 6 Gy irradiation, a short course of anti-CD154 mAb and 25 million fully allogeneic BALB/c bone marrow cells consistently produced long-term, stable, and multilineage chimerism in C57BL/6 recipients. Furthermore, chimeric mice displayed donor-specific transplantation tolerance, as BALB/c skin allografts were permanently accepted while third-party CBA/JCr skin allografts were promptly rejected. We next determined both the safety and efficacy of this protocol by infecting chimeric mice with lymphocytic choriomeningitis virus (LCMV) either at the time of transplantation or at several time points afterwards. Infection with LCMV at the time of transplantation prevented engraftment of allogeneic, but not syngeneic, bone marrow in similarly treated mice. Surprisingly, infected allograft recipients also failed to clear the virus and died. Post-mortem study revealed hypoplastic bone marrow and spleens. Hypoplasia and death in these mice required the combination of 6 Gy irradiation, LCMV infection on the day of transplantation, and an allogeneic bone marrow transplant but did not require the presence of anti-CDl54 mAb. Allochimeric mice infected with LCMV 15 days after transplantation were able to survive and maintain their bone marrow graft, indicating that the deleterious effects of LCMV infection on host and graft survival are confined to a narrow window of time during the tolerization and transplantation process. The final section of this thesis studied the mechanisms of graft rejection and death in sublethally irradiated recipients of allogeneic bone marrow and infection with LCMV at the time of bone marrow transplantation. Infection of interferon-α/β receptor knockout mice at the time of transplantation prevented the engraftment of allogeneic bone marrow, but the mice survived. Therefore, IFN-αβ is involved in the development of marrow hypoplasia and death, whereas a second mechanism is involved in blocking the development of chimerism in these mice. Through the use of depleting mAb's and knockout mice we demonstrate that three types of recipients survived and became chimeric after being given sublethal irradiation, anti-CD154 mAb, an allogeneic bone marrow transplant and a day 0 LCMV infection: mice depleted of CD8+ T cells, CD8 knockout mice, and TCR-αβ knockout mice. Our data indicate that the mediator of bone marrow allograft destruction in LCMV-infected mice treated with costimulatory blockade is a radioresistant CD8+ NK1.1- TCRαβ+ T cell. We conclude that a non-cytopathic viral infection at the time of transplantation can prevent engraftment of allogeneic bone marrow and result in the death of sub-lethally irradiated mice treated with costimulation blockade. The abrogation of allogeneic bone marrow engraftment is mediated by a population of CD8+ NK1.1- TCRαβ+ T cells and the mediator of hypoplasia and death is viral induction of IFN-αβ.
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Goldsmith, Paul Joseph. "1H NMR spectroscopic identification of non-invasive biomarkers of acute rejection and delayed graft function in renal transplantation." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/5901/.
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Delayed graft function (DGF) and acute rejection (AR) are complications after renal transplantation. It is impossible to differentiate between these clinically. Renal biopsy is the gold standard for diagnosis but is invasive and associated with complications. We aimed to identify early biomarkers, of DGF and AR in renal transplantation, which could lead to a diagnostic test that has no morbidity or mortality associated with its use. In total 163 from twenty-four patients using blood samples over several different pre and post-operative time-points were analysed. Plasma was extracted and analysed by 1H nuclear magnetic resonance spectroscopy (NMR). Spectra were interrogated using multivariate statistics, namely Principal component analysis (PCA) to reveal metabolites whose concentration varied as a function of kidney status. High performance liquid chromatography (HPLC) was used to validate and analyse molecules seen in the NMR studies. Until the third post-operative day, no differences were observed in the plasma metabolic profile of patients with DGF or AR in the NMR studies. From day four onwards molecules, trimethylamine-N-oxide and creatinine were found to vary in concentration across the patient groups in a way that correlated with the transplant outcome. In conclusion biomarkers exist in plasma which permit the discrimination between patients with DGF and AR, from day four following renal transplantation. These biomarkers are accessible, relatively non-invasive and without the morbidity associated with biopsy. A combination of these biomarkers presents the possibility of the development of a clinical diagnostic to improve clinical outcome.
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Li, Xiaosong. "The mechanism study of novel approaches to control chronic allograft rejection in rat orthotopic small bowel transplantation." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36395778.
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