Primary Nonfunction of Islet Grafts in Autoimmune Diabetic Nonobese Diabetic Mice Is Prevented by Treatment With Interleukin-4 and Interleukin-101

Abstract

In isologous islet transplantation in spontaneously diabetic nonobese (NOD) mice, destruction of the islet graft is caused by recurrence of T helper (Th)1-driven insulitis[fnc,1. We established a model of transplantation in which female NOD recipients were rendered diabetic by a single injection of cyclophosphamide (250 mg/kg). Under these conditions, 500 freshly isolated islets from young NOD mice transplanted under the kidney capsule did not lead to normoglycemia within 3 day after transplantation, but underwent immediate impairment of function. This primary nonfunction was seen in > 80% of the recipients. Treatment of the recipients with the Th2-associated cytokine interleukin (IL)-4 alone did not prevent primary nonfunction, whereas treatment of the recipients with a combination of IL-4 and IL-10 restored immediate function of the grafts. Cytokine treatment did not prevent later rejection of grafts. Histological analysis of the grafts revealed less severely infiltrated islets, with well preserved islet architecture, in only normoglycemic animals treated with IL-4 or with IL-4 and IL-10. Staining for lymphocytes, macrophages, and tumor necrosis factor (TNF)-alpha did not show differences between the groups, but IFN-gamma was markedly less expressed in IL-4- and IL-10-treated grafts. Concomitantly, analysis of animals treated for 8 days after injection of cyclophosphamide, with IL-4 and IL-10, revealed a reduction of IL-12 mRNA in the pancreas. We conclude from these data that primary nonfunction of islet grafts is prevented by treatment of the recipients with a combination of IL-4 and IL-10, via downregulation of Th1 cytokines.

Ingested interferon α suppresses Type I diabetes in non-obese diabetic mice

“…Transgenic IL-4 NOD mice were protected from insulitis and diabetes, a significantly higher ratio of mitogen-induced IFN-g/IL-4 was found in diabetic NOD mice but not in age-matched non-diabetic NOD mice and treatment of isologous islet transplants with the Type 2 T helper cell-associated cytokines IL-4 and IL-10 in spontaneously diabetic nonobese recipients restored immediate function of the grafts [16,22,23]. Induction of functional tolerance to islet antigens is indicated by the failure of diabetogenic spleen cells to induce diabetes in transgenic NOD-IL-4 recipients.…”

“…Immunohistochemistry studies showed that IL-10/Fc treatment promoted expression of IL-4 and IL-10, type 2 T helper cytokines, by isletinfiltrating leucocytes [25]. Primary non-function of islet grafts is prevented by treating the recipients with a combination of IL-4 and IL-10, via downregulation of type 1 T helper cytokines [22].…”

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

“…The low frequency of islet grafting is dependent on poor islet recovery from donors [4] and early islet loss during the first hours after grafting [5,6], termed primary graft nonfunction. Islet transplantation exposes cells to a variety of stressful stimuli, notably proinflammatory cytokines that encourage beta cell death and lead to early graft failure [7][8][9]. The reduction in islet mass immediately after transplantation implicates beta cell death by apoptosis and the prerecruitment of intracellular death-signalling pathways [10][11][12].…”

Intracellular Stress Signaling Pathways Activated During Human Islet Preparation and Following Acute Cytokine Exposure

“…Indeed, the islet isolation procedure itself destroys cellular and noncellular components of the pancreas that probably play a role in supporting islet survival (10,12). Further islet transplantation exposes cells to a variety of stressful stimuli, notably proinflammatory cytokines that encourage ␤-cell death and lead to early graft failure (13)(14)(15). Regardless of the molecular mechanisms involved, a reduction in islet ␤-cell mass after transplantation implicates islet ␤-cell death by apoptosis and the prerecruitment of intracellular deathsignaling pathways (16,17).…”