Background: A major barrier for islet transplantation is the lack of an immunotherapy to control both the allo- and autoimmune responses. Methods: In this study, we treated NOD mice with an anti-TCRΒ mAb before or after onset of type 1 diabetes (T1D) or upon receiving Balb/c islet allografts and monitored blood glucose levels. Results: Transient treatment with anti-TCRΒ mAb at 8 weeks of age prevented the development of T1D in 9 out of 10 normoglycemic NOD mice. Moreover, brief treatment with anti-TCRΒ mAb after onset of T1D (defined as 2 consecutive blood glucose readings of ≥ 250 mg/dL) induced remission in 6 out of 8 NOD mice. In the streptozotocin (STZ)-induced diabetic islet transplant model, normal glucose homeostasis was restored in C57BL/6 recipients treated transiently with anti-TCRΒ mAb with significant prolongation of BALB/c islet graft survival (93.1 ± 30.0 days) with 2 out of 7 recipients surviving indefinitely compared to control recipients (15.6 ± 1.7 days; p < 0.05). These recipients demonstrated reduced anti-donor responses in mixed lymphocyte reaction cultures and reduced production of anti-donor antibodies in serum compared to untreated recipients. Overtly diabetic NOD mice (blood glucose > 500 mg/dL) were transplanted with BALB/c islet allografts and treated with a short course of anti-TCRΒ mAb. This transient anti-TCRΒ mAb treatment resulted in significant prolongation of graft survival with a mean survival time of 28.0 ± 7.7 days compared to 8.7 ± 0.6 days in the untreated controls (p < 0.05) and did not elicit the severe cytokine release of inflammatory cytokines (IL2, INFΓ, TNFΑ, IL6) as seen with anti-CD3 mAb, demonstrating the safety of this antibody therapy. In addition, CD4+ T cells in the anti-TCRΒ mAb treated NOD mice displayed enhanced expression of PD-1, a marker of T cell exhaustion. Conclusion: anti-TCRΒ mAb therapy restores self-tolerance in spontaneously diabetic NOD mice and significantly prolongs islet allograft survival in diabetic NOD and C57BL/6 mice. These results demonstrate the potential of anti-TCRΒ mAbs as an induction therapy in islet transplantation.
To cite this abstract in AMA style:Schroder P, Khattar M, Deng R, Baum C, Mierzejewska B, Stepkowski S. TCR-Directed Immune Therapy Restores Self Tolerance and Significantly Prolongs Islet Allograft Survival in Diabetic NOD Mice [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/tcr-directed-immune-therapy-restores-self-tolerance-and-significantly-prolongs-islet-allograft-survival-in-diabetic-nod-mice/. Accessed September 23, 2017.
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