Pancreatic islet xenotransplantation: Barriers and prospects

Rayat, Gina R.; Gill, Ronald G.

doi:10.1007/s11892-003-0027-8

Cited by 20 publications

(17 citation statements)

References 48 publications

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“…Importantly, therapies that are effective in promoting islet allograft survival and tolerance can show similar efficacy in promoting xenograft survival. It is unclear whether similar results can be achieved in large animal models in which vigorous innate immune responses and/or preexisting xenoreactive natural antibodies are likely to comprise a more stringent barrier to xenograft survival (45). However, our results indicate that strategic simultaneous targeting of differing immune pathways can be highly efficacious in preventing the rejection of NPI xenografts and that such approaches may form an important future component of therapeutic regimens applied in clinical islet xenotransplantation.…”

Section: Anti-lfa-1 and Islet Xenograft Prolongationmentioning

confidence: 68%

“…Unlike allograft rejection that is independent of host MHC class II expression, porcine xenograft rejection was found to be entirely dependent on this indirect pathway (2). Importantly, T-cell-dependent antibody responses to allografts or xenografts are presumptive evidence of this "indirect" antigen recognition since T-B-cell collaboration requires interaction of helper T-cells, with antigens acquired and presented by the specific B-cell (45). We have frequently found that islet xenografts demonstrate an exaggerated antibody response relative to allografted animals, suggestive of strong indirect T-cell reactivity in vivo (R.G.G.…”

Section: Anti-lfa-1 and Islet Xenograft Prolongationmentioning

confidence: 99%

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Indefinite Survival of Neonatal Porcine Islet Xenografts by Simultaneous Targeting of LFA-1 and CD154 or CD45RB

Rayat

Gill

2005

Diabetes

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A variety of transient therapies directed against molecules involved in T-cell activation and function result in long-term islet allograft survival. However, there are relatively few examples of durable islet xenograft survival using similar short-term approaches, especially regarding highly phylogenetically disparate xenograft donors. Previous studies demonstrate that combined anti-lymphocyte function-associated antigen-1 (LFA-1) plus anti-CD154 therapy results in a robust form of islet allograft tolerance not observed with either individual monotherapy. Thus, the aim of this study was to determine whether the perturbation of anti-LFA-1, either alone or in combination with targeting CD154 or CD45RB, would promote neonatal porcine islet (NPI) xenograft survival in mice. NPI xenografts are rapidly rejected in wild-type C57BL/6 mice but reproducibly mature and restore durable euglycemia in diabetic, immune-deficient C57BL/6 rag-1 Ϫ/Ϫ recipients. A short course of individual anti-LFA-1, anti-CD154, or anti-CD45RB therapy resulted in long-term (>100 days) survival in a moderate proportion of C57BL/6 recipients. However, simultaneous treatment with anti-LFA-1 plus either anti-CD154 or anti-CD45RB therapy could achieve indefinite xenograft function in the majority of recipient animals. Importantly, prolongation of islet xenograft survival using combined anti-LFA-1/anti-CD154 therapy was associated with little mononuclear cell infiltration and greatly reduced anti-porcine antibody levels. Taken E ndocrine replacement therapy by islet transplantation is an attractive alternative treatment for patients with type 1 diabetes. However, the widespread clinical application of this treatment is currently limited by the shortage of human cadaveric organs available for transplantation. Transplantation of islets derived from pigs may be one approach that could solve the shortage in human islets, provided that formidable xenograft rejection can be prevented. Neonatal pigs in particular are an attractive inexpensive alternative source of insulin-producing tissue for clinical transplantation. Single neonatal pig donors yield ϳ50,000 islet cell aggregates that consist primarily of epithelial cells and pancreatic endocrine cells (1). Importantly, neonatal porcine islets (NPIs) are responsive to glucose challenge in vitro and are capable of maturing and reversing hyperglycemia in immune-deficient animals (1). Although neonatal pig shows promise in providing an abundant number of islets for clinical transplantation, we have recently reported that NPI xenografts are vigorously rejected when transplanted into untreated mice (2). Thus, the potential of neonatal pigs as a source of insulin-producing tissue for clinical transplantation is greatly hampered by a formidable cellular xenograft response. While a number of short-term approaches to blocking/perturbing a variety of cell surface molecules involved in T-cell function can result in longterm islet allograft survival, it is less clear whether T-celldirected therapies can result in prolo...

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Section: Anti-lfa-1 and Islet Xenograft Prolongationmentioning

confidence: 68%

Section: Anti-lfa-1 and Islet Xenograft Prolongationmentioning

confidence: 99%

Indefinite Survival of Neonatal Porcine Islet Xenografts by Simultaneous Targeting of LFA-1 and CD154 or CD45RB

Rayat

Gill

2005

Diabetes

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“…While fully immune competent transplant recipients possess a broad repertoire of pathways available to mount a response to non-self tissue, it is becoming increasingly apparent that the characteristics of xenograft immunity depend both on the tissue/organ grafted and the specific type of phylogeneic difference between donor and recipient [6, 14]. Therefore, one must examine the requirements for T-cell-dependent xenograft rejection using defined tissues/organs of interest and particular inter-species transplant combinations.…”

Section: Discussionmentioning

confidence: 99%

“…Studies based on the removal or reduction of antibodies or antibody responses show promise [2–5]. However, even if hyperacute rejection can be prevented, adaptive T-cell dependent humoral and cellular mechanisms are capable of aggressive xenograft rejection [6, 7]. The role of CD4 + T-cells in the rejection of cardiac allografts and xenografts is well established.…”

Section: Introductionmentioning

confidence: 99%

CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

Plenter¹,

Grazia²,

Doan³

et al. 2012

The Journal of Heart and Lung Transplantation

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Background Previous studies indicate that acute CD4 T-cell-mediated cardiac allograft rejection requires donor MHC class II expression and can be independent of ‘indirect’ antigen presentation. However, other studies suggest that indirect antigen presentation to CD4 T-cells may play a primary role in cellular xenograft immunity. Thus, the relative roles of direct/indirect CD4 T-cell reactivity against cardiac xenografts is unclear. We set out to determine the role for indirect CD4 T-cell reactivity in cardiac xenograft rejection. Methods Rat hearts were transplanted heterotopically into wild-type and immuno-deficient mice. Recipients were untreated, treated with depleting antibodies or reconstituted with wild-type cells. Results Antibody depletion confirmed that rat heart xenograft rejection in C57Bl/6 mice was CD4 T-cell-dependent. Also, heart xenografts survived long-term in B6 MHC class II (C2D) deficient mice. Graft acceptance in C2D mice was not secondary to CD4 T-cell deficiency alone, because transferred B6 CD4 T-cells failed to trigger rejection in C2D hosts. Furthermore, purified CD4 T-cells were sufficient for acute rejection of rat heart xenografts in immune-deficient B6rag1−/− recipients. Importantly, CD4 T-cells did not reject rat hearts in C2Drag1−/− hosts, contrasting results using cardiac allografts. ‘Direct’ xenoreactive CD4 T-cells were not sufficient to mediate rejection despite vigorous reactivity to rat stimulator cells in vitro. Conclusion Taken together, results show that CD4 T-cells are both necessary and sufficient for acute cardiac xenograft rejection and host MHC class II is critical in this process.

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“…T lymphocytes play an important role not only in chronic rejection but also in acute rejection of heart transplants . Adaptive T cells relying on humoral and cellular mechanisms can actively induce xenograft rejection . The role of CD4 + T cells in the rejection of heart transplants has been well established.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of α‐enolase in acute rejection of cardiac transplant in rat model: Implications for the secretion of interleukin‐17

Shi

Yang

et al. 2014

Pediatric Transplantation

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Acute allograft rejection remains a major problem in solid organ transplantation. The enzyme α-enolase has been shown to induce an immune response in cardiac transplantation. In this study, we investigated the role of α-enolase in acute allograft rejection in a rat model of heart transplantation. Hearts from either (WF: RT1(u) ) or (Lew: RT1(1) ) rats were transplanted into (Lew: RT1(1) ) rats. No rejection occurred in the isograft group, for which the median survival time was >168 days, whereas the median survival time of the allograft group was significantly less at 10 ± 2.1 days (n = 8 per group, p < 0.001). Increased inflammation was observed in allografts, including increased α-enolase expression and increased numbers of infiltrating CD4(+) T cells (p < 0.05). By immunohistochemical staining, we confirmed that α-enolase was expressed not only in myocardial cells but also in the infiltrating lymphocytes. However, on the fifth day after transplantation, α-enolase expression was no longer observed in the lymphocytes (n = 3, p < 0.001). In contrast, no lymphocytes were found in isografts after transplantation (n = 3, p < 0.001). α-enolase expression was increased in lymphocytes, which are implicated in the acute rejection of cardiac transplants. Intragraft α-enolase inhibition may be useful as an adjuvant therapy to systemic immunosuppression in heart transplantation.

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Pancreatic islet xenotransplantation: Barriers and prospects

Cited by 20 publications

References 48 publications

Indefinite Survival of Neonatal Porcine Islet Xenografts by Simultaneous Targeting of LFA-1 and CD154 or CD45RB

Indefinite Survival of Neonatal Porcine Islet Xenografts by Simultaneous Targeting of LFA-1 and CD154 or CD45RB

CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

Upregulation of α‐enolase in acute rejection of cardiac transplant in rat model: Implications for the secretion of interleukin‐17

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