Transfer of dendritic cells (DC)ex vivostimulated with interferon-gamma (IFN-γ) down-modulates autoimmune diabetes in non-obese diabetic (NOD) mice

Abstract

The NOD mouse has been used to explore the many features of insulin-dependent diabetes mellitus (IDDM) that is caused by the destruction of insulin-producing beta cells in the islets of Langerhans of the pancreas. Self-reactive T cells have been considered to mediate IDDM in the NOD mouse, and antigen-presenting cells like DC and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. The present study shows that transfer of IFN-gamma-stimulated DC of the NOD or ICR mouse into the NOD mouse did not accelerate IDDM onset but afforded long-lasting protection against clinical and histological signs of IDDM in the recipient mice. The anti-diabetogenic ability was unique to IFN-gamma-stimulated DC when compared with unstimulated DC. A considerable proportion of the injected IFN-gamma-stimulated DC was demonstrated to migrate into the pancreas and its associated lymphoid tissues, suggesting the DC exert their anti-diabetogenic effects there. These findings suggest that development of autoimmune diabetes in the NOD mouse is under the control of DC, and that IDDM onset could be controlled by appropriately manipulating DC systems in vivo, which may open the gate for the therapeutic application of ex vivo-conditioned DC to human IDDM.

Autoantigen-specific protection of non-obese diabetic mice from cyclophosphamide-accelerated diabetes by vaccination with dendritic cells

“…Studies in other autoimmune diseases such as experimental autoimmune encephalomyelitis and collagen-induced arthritis also reported on a specific prevention of disease development after DC vaccination [17,40,41]. However, in contrast to our observation, previous studies have shown an autoantigen-unspecific protection from diabetes after transfer of DCs in NOD mice [19,20,21]. These inconsistent results could be due to differences in the origin of the DCs, the culture condition chosen and the pre-treatment with IL-10.…”

“…Protection from diabetes was observed in NOD mice after immunisation with DCs from the local pancreatic lymph nodes [17]. In addition, intraperitoneal injection of DCs isolated from the spleen or bone marrow was found to reduce the incidence of diabetes in NOD mice whether or not the DCs were pulsed with autoantigen [19,20,21]. The unspecific immunomodulatory effect has been explained by a general activation of Th2 cells following DC administration.…”

Salmonella typhimurium Infection in Nonobese Diabetic Mice Generates Immunomodulatory Dendritic Cells Able to Prevent Type 1 Diabetes

“…These include the use of cultured, bone marrow-derived DCs to prevent T1D (14), genetic manipulation of DCs to prevent T1D or collagen-induced arthritis (16,17), or exposure to immunomodulators including TNF-␣ (18) or TGF-␤ (24) to prevent experimental autoimmune encephalitis and experimental autoimmune myasthenia gravis, respectively. In particular, exposure ex vivo to IFN-␥ has been shown to generate DCs that ameliorate experimental autoimmune encephalitis (25) or T1D (15). Given the sustained high levels of IFN-␥ production we have shown in the spleen, PLN, and pancreas of NOD mice after S. typhimurium infection (4), our observations may represent an important in vivo correlate.…”

“…Observations suggest that only a small fraction of labeled DCs can be recovered from major organs 24 h after injection, presumably representing a high level of cell death after transfer (T. Raine, unpublished observations) (15). Overall, it seems that the number of injected DCs that traffic to the PLN is probably very small indeed.…”

Tolerogenic Dendritic Cells for Therapy of Immune-Mediated Inflammatory Diseases

“…It has been shown that the active metabolite of vitamin D can induce TDCs that inhibits NOD mice diabetes development by increasing the function of Tregs (Adorini, Penna et al 2003). Furthermore, DCs treated ex-vivo with IFN-, a pleiotropic cytokine with both immunostimulatory and immunoregulatory functions, act in an immunosuppressive manner after in vivo transfer (Shinomiya, Fazle Akbar et al 1999). Such IFN--treated TDCs were demonstrated to successfully migrate into the pancreas and associated lymphoid tissues, an important feature desired in the generation of both DCs as positive (tumor vaccines) and negative vaccination tools.…”