Differences in suppressor of cytokine signaling-1 (SOCS-1) expressing islet allograft destruction in normal BALB/c and spontaneously-diabetic NOD recipient mice

Michelle Solomon, Malin Flodström-Tullberg, Nora Sarvetnick

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Background. The ability to block Interferon signaling represents an important strategy in designing therapies to prevent beta-cell destruction during islet allograft rejection. Methods. The SOCS proteins regulate cytokine signaling by blocking activation of JAK/STAT proteins. Using islets isolated from SOCS-1 transgenic mice (SOCS-1-Tg; these mice express SOCS-1 under the control of the human insulin promoter and are on the C57BL6/J background), we investigated whether SOCS proteins can prevent the destruction pancreatic islet cells transplanted beneath the kidney capsule of major histocompatibility complex mismatched normal BALB/c and spontaneously-diabetic NOD mouse recipients. Results. Immunohistochemical staining for insulin confirmed the presence of donor SOCS-1-Tg islets in islet allografts harvested at 22 days posttransplant, whereas grafts of control non-Tg islets were destroyed by 14 days. In contrast, SOCS-1-Tg allogeneic islets were not protected from beta-cell destruction in clinically diabetic NOD mice. The islet allografts functioned for 1 week posttransplant; however, hyperglycemia returned after 2 weeks and the grafts were destroyed. Rejection of SOCS-1-Tg and non-Tg islets in autoimmune diabetic NOD mice was associated with an infiltrate of both CD4+ and CD8+ T cells and a T2-type cytokine response (IL-4) rather than the conventional T1-type cytokine response observed during islet allograft rejection. Self-antigen upregulation in response to IFN-γ stimulation did not appear to be a factor in rejection of the islet allografts. Conclusions. These results demonstrate that expression of SOCS-1 in islets delays islet allograft rejection but cannot circumvent destruction of the islets by the recurrence of the tissue-specific autoimmune process of spontaneous diabetes.

Original languageEnglish (US)
Pages (from-to)1104-1109
Number of pages6
JournalTransplantation
Volume79
Issue number9
DOIs
StatePublished - May 15 2005

Keywords

  • Cytokines
  • Experimental transplantation
  • Islets
  • SOCS-1
  • Transplantation immunology and immunobiology

ASJC Scopus subject areas

  • Transplantation

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