Prevention of Recurrence of IDDM in Islet-Transplanted Diabetic NOD Mice by Adjuvant Immunotherapy

Abstract

Insulin-dependent diabetes mellitus (IDDM) involves the destruction of the insulin-producing cells in the islets of Langerhans. One possible cure is by transplanting the islet cells; however, transplanted islets, even between identical twins, are subject to autoimmune destruction by the disease process, resulting in diabetes recurrence. We recently reported that complete Freund's adjuvant (CFA), an immunomodulating agent, prevented development of autoimmune diabetes in the NOD mouse. In this study, we evaluated adjuvant therapy in prevention of autoimmune destruction and rejection of transplanted islets in diabetic NOD mice. After transplantation, untreated syngeneic islet recipients (n = 16) initially became normoglycemic and then hyperglycemic, with a median survival time (MST) of the graft of 17 days. When CFA was administered at the time of transplantation, 11 of 13 CFA-treated syngeneic islet recipients remained normoglycemic long term (>100 days) with an MST >107 days. Ten of 11 mice maintained indefinite normoglycemia until the conclusion of follow-up (101 to 172 days). When adjuvant therapy was used in conjunction with allogeneic islet transplantation, graft survival was not extended, with MST being similar to the untreated allogeneic islet recipients (12 [n = 5] and 13 [n = 5] days, respectively). The extended acceptance of second syngeneic islet grafts by CFA-treated mice indicates that the persistent autoimmunity against the transplanted islets can be reversed in the diabetic NOD mice after CFA treatment.

Reversal of established autoimmune diabetes by restoration of endogenous β cell function

“…in nonautoimmune diabetic hosts (6), the survival time of islets from β 2 M -/-C57 mice in diabetic NOD females (group C) was only about three times that of normal C57 islets. As expected from previous observations (2,32), treatment with CFA prolonged the survival of syngeneic islet grafts in diabetic NOD hosts (group D) but had a minimal effect on the survival of C57 islets (group E), which were uniformly rejected by 11 days after transplantation. However, the combination of β 2 M -/-C57 islet transplants with CFA treatment resulted in sustained (>129 days) normoglycemia in 5 of 14 diabetic NOD hosts (group F).…”

“…The increased susceptibility to apoptosis of misselected T cells that result from improper education by MHC class I peptide complexes suggested that the production of TNF-α in vivo might promote the selective death of such poorly educated lineages (10,26,27). Furthermore, treatment of diabetic NOD mice or BB rats with CFA, an inducer of TNF-α production, both impairs the transfer of disease by T cells from these animals to naive hosts (28)(29)(30)(31) as well as prolongs the survival of syngeneic islet grafts in spontaneously diabetic hosts (2,32). We therefore hypothesized that CFA treatment might eliminate, at least temporarily, the autoreactive lymphoid cells of NOD mice by promoting their apoptosis, in part through the induction of TNF-α.…”

Th17 Polarized Cells from Nonobese Diabetic Mice Following Mycobacterial Adjuvant Immunotherapy Delay Type 1 Diabetes

“…We found that a CD4 + CD8 + CD25 + Treg clone derived from the LN cells of NOD mice immunized with CFA is capable of suppressing the immune response by secreting Granzyme B/Perforin in a cell contact-independent manner (9). Apoptosis of diabetogenic T cells has been suggested as another mechanism for the prevention of the recurrence of diabetes in islet-transplanted NOD mice (17,18). BCG downregulates destructive autoimmunity by TNF-a/IFN-g-induced apoptosis of diabetogenic T cells through both Fas and TNF pathways (17).…”

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

“…A number of researchers have identified strategies for the treatment and prevention of diabetes in NOD mice [21][22][23][24][25][26][27][28][29][30][31][32][33]. For example, anti-CD3 treatment in NOD mice formed the basis for a clinical trial of anti-CD3 monoclonal antibody therapy in human T1D models.…”