Immunotherapy With Nondepleting Anti-Cd4 Monoclonal Antibodies but Not Cd28 Antagonists Protects Islet Graft in Spontaneously Diabetic Nod Mice From Autoimmune Destruction and Allogeneic and Xenogeneic Graft Rejection1

Guo, Zhixin; Wu, Tao; Kirchhof, Nicole; Mital, Deepak; Williams, James W.; Azuma, Miyuki; Sutherland, David E.R.; Hering, Bernhard J.

doi:10.1097/00007890-200106150-00027

Cited by 41 publications

(25 citation statements)

References 48 publications

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“…Investigations have probably been hampered by the complexity of the process in the NOD mouse strain, because possible recurrence of the autoimmune response (12,18,21,42) and the unique type of immunologic responses mounted by these mice (29) are additional factors to be considered. The role of T cells has been confirmed in several studies; immunotherapy with short-term depletion of CD4 ϩ T cells (18) or treatment with nondepleting anti-CD4 mAb (43) prolonged islet allograft survival, suggesting an important role for the CD4 ϩ T cell subpopulation. Studies have also suggested a role for the CD4 ϩ T cell direct pathway in islet allograft rejection, by demonstrating that transplantation of MHC class II-deficient islets (20) or oxygen-precultured islet allografts (21-24) resulted in marginal but significant prolongation of islet allograft survival (12).…”

Section: Discussionmentioning

confidence: 87%

Allorecognition and Effector Pathways of Islet Allograft Rejection in Normal versus Nonobese Diabetic Mice

Makhlouf¹,

Yamada²,

Ito

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Islet transplantation is becoming an accepted therapy to cure type I diabetes mellitus. The exact mechanisms of islet allograft rejection remain unclear, however. In vivo CD4 ϩ and CD8 ϩ T cell-depleting strategies and genetically altered mice that did not express MHC class I or class II antigens were used to study the allorecognition and effector pathways of islet allograft rejection in different strains of mice, including autoimmunity-prone nonobese diabetic (NOD) mice. In BALB/c mice, islet rejection depended on both CD4 ϩ and CD8 ϩ T cells. In C57BL/6 mice, CD8ϩ T cells could eventually mediate islet rejection by themselves, but they produced rejection more efficiently with help from CD4 ϩ T cells stimulated through either the direct or indirect pathway. In C57BL/6 mice, CD4ϩ T cells alone caused islet rejection when only the direct pathway was available but not when only the indirect pathway was available. In contrast, in NOD mice, CD4ϩ T cells alone, with only the indirect pathway, could mediate islet and cardiac allograft rejection. These findings indicate that different mouse strains can make use of different pathways for T cell-mediated rejection of islet allografts. In addition, they demonstrate that NOD mice, which develop autoimmunity and are known to be resistant to tolerance induction, have an unusually powerful CD4 ϩ cell indirect mechanism that can cause rejection of both islet and cardiac allografts. These data shed light on the mechanisms of islet allograft rejection in different responder strains, including those with autoimmunity.

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Section: Discussionmentioning

confidence: 87%

Allorecognition and Effector Pathways of Islet Allograft Rejection in Normal versus Nonobese Diabetic Mice

Makhlouf¹,

Yamada²,

Ito

et al. 2003

Journal of the American Society of Nephrology

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“…on day 0 and day 2 post transplant. CTLA4Ig, which was obtained from a Chinese hamster ovary cell line that secreted CTLA4Ig fusion protein as previously published, 10 was given at 0.5 mg i.p. on day 2 post transplant.…”

Section: Treatmentmentioning

confidence: 99%

Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy

Sozen

Luo

et al. 2002

Bone Marrow Transplant

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“…These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process. Diabetes 58: 165-173, 2009 T he NOD mouse is a model of type 1-like autoimmune diabetes and is used to study costimulation blockade-based transplantation tolerance within the context of autoimmunity (1)(2)(3)(4). However, costimulation blockade protocols fail in NOD mice.…”

mentioning

confidence: 99%

IddLoci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

et al. 2009

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OBJECTIVE-NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade-based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.RESEARCH DESIGN AND METHODS-To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes. RESULTS-The frequency of diabetes is reduced in NOD.B6Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD ϫ CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2 g7 ϫ CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival. CONCLUSIONS-Il2is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process. Diabetes 58: [165][166][167][168][169][170][171][172][173] 2009

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Immunotherapy With Nondepleting Anti-Cd4 Monoclonal Antibodies but Not Cd28 Antagonists Protects Islet Graft in Spontaneously Diabetic Nod Mice From Autoimmune Destruction and Allogeneic and Xenogeneic Graft Rejection1

Abstract: Nondepleting anti-CD4 mAbs but not CD28 antagonists protect islet grafts in diabetic NOD mice from autoimmune destruction and allogeneic and xenogeneic graft rejection. The efficacy of nondepleting anti-CD4 mAbs is compromised when it combines with CTLA4Ig.

Cited by 41 publications

References 48 publications

Allorecognition and Effector Pathways of Islet Allograft Rejection in Normal versus Nonobese Diabetic Mice

Allorecognition and Effector Pathways of Islet Allograft Rejection in Normal versus Nonobese Diabetic Mice

Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy

IddLoci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

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