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Selective depletion of alloreactive T cells leads to long-term islet allograft survival across a major histocompatibility complex mismatch in diabetic mice

Journal Article


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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.

Authors


  •   Hu, Min (external author)
  •   Wu, J (external author)
  •   Zhang, Geoff Yu. (external author)
  •   Wang, Yuan-Min (external author)
  •   Watson, Debbie
  •   Yi, S (external author)
  •   Hawthorne, W J. (external author)
  •   O'Connell, Philip J. (external author)
  •   Alexander, Stephen I. (external author)

Publication Date


  • 2013

Citation


  • Hu, M., Wu, J., Zhang, G. Y., Wang, Y., Watson, D., Yi, S., Hawthorne, W. J., O'Connell, P. J. & Alexander, S. I. (2013). Selective depletion of alloreactive T cells leads to long-term islet allograft survival across a major histocompatibility complex mismatch in diabetic mice. Cell Transplantation, 22 (10), 1929-1941.

Scopus Eid


  • 2-s2.0-84884696973

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2130&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1112

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 1929

End Page


  • 1941

Volume


  • 22

Issue


  • 10

Place Of Publication


  • United States

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.

Authors


  •   Hu, Min (external author)
  •   Wu, J (external author)
  •   Zhang, Geoff Yu. (external author)
  •   Wang, Yuan-Min (external author)
  •   Watson, Debbie
  •   Yi, S (external author)
  •   Hawthorne, W J. (external author)
  •   O'Connell, Philip J. (external author)
  •   Alexander, Stephen I. (external author)

Publication Date


  • 2013

Citation


  • Hu, M., Wu, J., Zhang, G. Y., Wang, Y., Watson, D., Yi, S., Hawthorne, W. J., O'Connell, P. J. & Alexander, S. I. (2013). Selective depletion of alloreactive T cells leads to long-term islet allograft survival across a major histocompatibility complex mismatch in diabetic mice. Cell Transplantation, 22 (10), 1929-1941.

Scopus Eid


  • 2-s2.0-84884696973

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2130&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1112

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 1929

End Page


  • 1941

Volume


  • 22

Issue


  • 10

Place Of Publication


  • United States