Induction of tolerance and prolongation of islet allograft survival by syngeneic hematopoietic stem cell transplantation in mice

Transpl Immunol. 2015 Oct;33(2):130-9. doi: 10.1016/j.trim.2015.08.004. Epub 2015 Aug 24.

Abstract

Backgrounds: Syngeneic or autologous hematopoietic stem cells transplantation (HSCT) has been proposed to treat autoimmune diseases because of its immunosuppressive and immunomodulatory effects, which can also contribute to posttransplant antirejection therapy. In this study, we explored the tolerogenic effect of syngeneic HSCT on prolonging islet allograft survival.

Methods: C57BL/6 mice received syngeneic HSCT plus preconditioning with sublethal irradiation. Then islets of BALB/c mice were transplanted into the renal subcapsular of C57BL/6 mice after chemically induced into diabetes.

Results: HSCT mice exhibited improved islet allograft survival and increased serum insulin compared to control mice. Islet allografts of HSCT mice displayed lower level lymphocyte infiltration and stronger insulin staining than control mice. T cells of HSCT mice proliferated poorly in response to allogeneic splenocytes compared to control mice. Mice appeared reversed interferon-γ (IFN-γ)/interleukin-4 (IL-4) ratio to a Th2 immune deviation after syngeneic HSCT. The percentage of CD8(+) T cells was lower, while percentage of CD4(+)CD25(+)Foxp3(+) T regulatory cells (Tregs) was higher in HSCT mice than control mice. HSCT mice showed higher percentage of CTLA-4(+) T cells and expression of CTLA-4 mRNA than control mice. Targeting of CTLA-4 by intraperitoneal injection of anti-CTLA-4 mAb abrogated the effect of syngeneic HSCT on prolonging islet allograft survival, inhibiting activity of T cells in response to alloantigen, promoting Th1 to Th2 immune deviation and up regulating CD4(+)CD25(+)Foxp3(+) Tregs.

Conclusions: Syngeneic HSCT plus preconditioning of sublethal irradiation induces tolerance and improves islet allograft survival in fully mismatched mice model. Th1 to Th2 immune deviation, increased CD4(+)CD25(+)Foxp3(+) Tregs and up-regulation of CTLA-4 maybe contribute to the tolerogenic effect induced by syngeneic HSCT.

Keywords: Cell survival; Hematopoietic stem cell; Immune tolerance; Islet graft; Syngeneic transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism
  • Cells, Cultured
  • Diabetes Mellitus / chemically induced
  • Diabetes Mellitus / immunology
  • Diabetes Mellitus / therapy*
  • Forkhead Transcription Factors / metabolism
  • Graft Survival / drug effects
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Islets of Langerhans Transplantation*
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Th1-Th2 Balance / drug effects
  • Transplantation Conditioning / methods*
  • Transplantation Tolerance / drug effects

Substances

  • Antibodies, Blocking
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse