Selective Depletion of Alloreactive T Cells Leads to Long-Term Islet Allograft Survival across a Major Histocompatibility Complex Mismatch in Diabetic Mice. Issue 10 (October 2013)

• Record Type: Journal Article
• Authors: Hu, M.; Wu, J.; Zhang, G. Y.; Wang, Y. M.; Watson, D.; Yi, S.; Hawthorne, W. J.; O'connell, P. J.; Alexander, S. I.
• Is Part Of: Cell transplantation. Volume 22:Issue 10(2013)
• Page Start: 1929
• Page End: 1941
• Publication Date: 2013-10
• Subjects: Islet cell transplantation; -- Long-term islet allograft survival; -- Depletion of alloreactive CD3+ T cells; -- T-cell repertoire; -- Type 1 diabetes; Cell transplantation -- Periodicals; Cell Transplantation; Cell transplantation; Electronic journals; Periodicals; Periodicals; 571.638
• DOI: 10.3727/096368912X658025
• Languages: English
• ISSNs: 0963-6897

Abstract

Islet cell transplantation as a therapy for type 1 diabetes has been limited by progressive graft loss. Significant immunosuppression including T-cell ablation has been used in an attempt to limit islet rejection. Here, we show that CD3 + lymphocytes depleted of alloreactive T cells selected from a mixed lymphocyte reaction (MLR), where responder BALB/c splenocytes stained with carboxyfluorescein succinimidyl ester (CFSE) were stimulated with irradiated C57BL/6 splenocytes for 5 days, infused into diabetic immunodeficient mice are capable of restoring a broad T-cell repertoire and specifically do not reject islet transplants from the strain (C57BL/6) used in the original depletion. These mice demonstrate reconstitution with CD4 + and CD8 + T cells, the capacity to reject third-party grafts (CBA), and restoration of interferon-γ (IFN-γ) responses to third-party alloantigens. Over time, both forkhead box P3-positive (Foxp3 + ) T regulatory cells (Tregs) and γδ T cells expand, suggesting a role for peripheral tolerance, in addition to the initial depletion of alloreactive T cells, in long-term islet graft survival. Our results suggest that immune restoration with CD3 + lymphocytes where alloreactive T cells are removed can restore cognate immunity without islet allograft loss and recurrence of diabetes.