Immunosuppressive Effects of Streptozotocin-Induced Diabetes Result in Absolute Lymphopenia and a Relative Increase of T Regulatory Cells

Abstract

OBJECTIVEStreptozotocin (STZ) is the most widely used diabetogenic agent in animal models of islet transplantation. However, the immunomodifying effects of STZ and the ensuing hyperglycemia on lymphocyte subsets, particularly on T regulatory cells (Tregs), remain poorly understood.RESEARCH DESIGN AND METHODSThis study evaluated how STZ-induced diabetes affects adaptive immunity and the consequences thereof on allograft rejection in murine models of islet and skin transplantation. The respective toxicity of STZ and hyperglycemia on lymphocyte subsets was tested in vitro. The effect of hyperglycemia was assessed independently of STZ in vivo by the removal of transplanted syngeneic islets, using an insulin pump, and with rat insulin promoter diphtheria toxin receptor transgenic mice.RESULTSEarly lymphopenia in both blood and spleen was demonstrated after STZ administration. Direct toxicity of STZ on lymphocytes, particularly on CD8+ cells and B cells, was shown in vitro. Hyperglycemia also correlated with blood and spleen lymphopenia in vivo but was not lymphotoxic in vitro. Independently of hyperglycemia, STZ led to a relative increase of Tregs in vivo, with the latter retaining their suppressive capacity in vitro. The higher frequency of Tregs was associated with Treg proliferation in the blood, but not in the spleen, and higher blood levels of transforming growth factor-β. Finally, STZ administration delayed islet and skin allograft rejection compared with naive mice.CONCLUSIONSThese data highlight the direct and indirect immunosuppressive effects of STZ and acute hyperglycemia, respectively. Thus, these results have important implications for the future development of tolerance-based protocols and their translation from the laboratory to the clinic.

IL-7 receptor blockade following T cell depletion promotes long-term allograft survival

“…Taken together, these data indicate that immunoregulation was established after a short course of IL-7R blockade. However, this model might overestimate the efficacy of IL-7R blockade because STZ has recently been demonstrated to induce lymphopenia associated with an increase in Treg frequency and produce immunosuppressive effects (35).…”

Streptozotocin-associated lymphopenia in cynomolgus monkeys

“…Acute hyperglycemia causes lymphopenia, 16,25 and a chronic insulin-deficient diabetic state is associated with decreased proliferation and differentiation of lymphoid cells. 26 The STZinduced immunosuppressive effect and that associated with hyperglycemia/diabetes may thus be additive.…”

“…11,12 In rodents, STZ has been reported to affect the immune system, being associated with bone marrow suppression, derangements in leukocyte count (leukopenia), and lymphocyte depletion in the blood and spleen, the mechanisms of which are not completely understood. [13][14][15][16] Direct and irreversible damage to the bone marrow and the early precursors of T cells is seen in STZ-treated mice. 17 Levine et al studied the toxicological effects of STZ in mice and in large animals (dogs and rhesus monkeys), and reported necrosis of lymphoid organs, and bone marrow hypoplasia.…”

Effects of Hibiscus sabdariffa Linn. Aqueous Extract on Oxidative Stress and T Lymphocyte Population in Spleen of Streptozotocin-induced Diabetic Rats

“…Kajian yang hampir sama oleh Muller et al (2011) juga mendapati kesan STZ mampu mengurangkan bilangan sel limpa. Walau bagaimanapun, mekanisme tindakan STZ dalam pengurangan sel limpa masih belum dikenal pasti secara spesifi k.…”