Immunosuppression Preventing Concordant Xenogeneic Islet Graft Rejection Is Not Sufficient to Prevent Recurrence of Autoimmune Diabetes in Nonobese Diabetic Mice

Guo, Zhixin; Mital, Deepak; Shen, Jikun; Chong, Anita S.; Foster, Patricia L.; Sankary, Howard; McChesney, Lawrence; Jensik, Stephen C.; Williams, James W.

doi:10.1097/00007890-199805270-00005

Cited by 19 publications

(15 citation statements)

References 38 publications

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“…islet allografts in chemically diabetic mice often prove themselves ineffective in diabetic NOD recipients (21,24,25). Consistent with these observations, we have reported that treatment with anti-CD154 mAb induced longterm survival of B6 islet allografts (Ͼ100 days) in young chemically induced diabetic NOD mice, in which no isletspecific autoimmunity occurs (21), whereas an identical therapeutic protocol resulted only in prolongation, without long-term survival, of islet allografts in spontaneously (autoimmune) diabetic NOD mice (21).…”

Section: Discussionsupporting

confidence: 59%

“…In NOD mice with already established autoimmune diabetes, few treatments lead to prolonged islet allograft survival, and even fewer lead to indefinite acceptance of the graft (22,23). Therapeutic approaches that result in longterm islet graft survival and even immunological tolerance in allogeneic combinations, in fact, often fail when tested in spontaneously diabetic NOD recipients (21,24,25).…”

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confidence: 99%

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Prolonged Islet Allograft Survival in Diabetic NOD Mice by Targeting CD45RB and CD154

et al. 2003

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1Clinical islet transplantation is a successful procedure that can improve the quality of life in recipients with diabetes. A drawback of the procedure is the need for chronic administration of immunosuppressive drugs that, among other side effects, are potentially diabetogenic. Definition of immunosuppressive protocols that utilize nondiabetogenic compounds could further improve islet transplantation outcome. We used the NOD mouse to assess the effect of targeting the T-lymphocyte surface receptors CD45RB and CD154 in preventing loss of allogeneic islet grafts as a result of recurrence of autoimmunity and allorejection. Administration of the two antibodies led to significantly prolonged allograft survival, with a percentage of grafts surviving longterm. The therapeutic efficacy of the treatment was paralleled by a shift in CD45RB isoform expression on T-lymphocytes, increased in vitro responsiveness to interleukin-7, and increased in vitro ␥-interferon production after anti-CD3 antibody stimulation. Furthermore, graft infiltration by CD8؉ T-cells was remarkably reduced. Recipient mice bearing functioning allografts were otherwise immunocompetent, as assessed in vivo and in vitro by numerous tests, including intragraft cytokine production, responsiveness to polyclonal stimulation and alloantigens, and analysis of cell subset phenotype. These data show that nondiabetogenic regimens of immunomodulation can lead to prolonged islet allograft survival in the challenging NOD mouse model. Diabetes 52:957-964, 2003

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Section: Discussionsupporting

confidence: 59%

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confidence: 99%

Prolonged Islet Allograft Survival in Diabetic NOD Mice by Targeting CD45RB and CD154

et al. 2003

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“…The islets were isolated according to a protocol that is similar to a previously published isolation protocol (3,4). Briefly, we injected 2.5 mL of Hank's balanced salt solution (HBSS, Life Technology, MD) containing 2 mg/mL collagenase from Clostridium histolyticum (Serva, Heildelberg, Germany) into the pancreatic duct.…”

Section: Islet Isolation and Transplantationmentioning

confidence: 99%

“…Islets free of acinar cells, vessels, lymph nodes and ducts were used for transplantation. Islet transplantation was performed as described previously (3,4). Briefly, the left kidney was exposed through a lumbar incision under sterile conditions.…”

Section: Islet Isolation and Transplantationmentioning

confidence: 99%

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Increasing Donor Chimerism and Inducing Tolerance to Islet Allografts by Post-Transplant Donor Lymphocyte Infusion

Liu

Hao

Pan

et al. 2006

American Journal of Transplantation

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Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.

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Immunomodulation

Faustman¹

2000

Principles of Tissue Engineering

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Immunosuppression Preventing Concordant Xenogeneic Islet Graft Rejection Is Not Sufficient to Prevent Recurrence of Autoimmune Diabetes in Nonobese Diabetic Mice

Cited by 19 publications

References 38 publications

Prolonged Islet Allograft Survival in Diabetic NOD Mice by Targeting CD45RB and CD154

Prolonged Islet Allograft Survival in Diabetic NOD Mice by Targeting CD45RB and CD154

Increasing Donor Chimerism and Inducing Tolerance to Islet Allografts by Post-Transplant Donor Lymphocyte Infusion

Immunomodulation

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