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* The Jackson Laboratory, Bar Harbor, ME 04609; and
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605
In both humans and NOD mice, particular combinations of MHC genes provide the primary risk factor for development of the autoreactive T cell responses causing type 1 diabetes (T1D). Conversely, other MHC variants can confer dominant T1D resistance, and previous studies in NOD mice have shown their expression on hemopoietically derived APC is sufficient to induce disease protection. Although allogeneic hemopoietic chimerization can clearly provide a means for blocking T1D development, its clinical use for this purpose has been obviated by a requirement to precondition the host with what would be a lethal irradiation dose if bone marrow engraftment is not successful. There have been reports in which T1D-protective allogeneic hemopoietic chimerization was established in NOD mice that were preconditioned by protocols not including a lethal dose of irradiation. In most of these studies, virtually all the hemopoietic cells in the NOD recipients eventually converted to donor type. We now report that a concern about such full allogeneic chimeras is that they are severely immunocompromised potentially because their T cells are positively selected in the thymus by MHC molecules differing from those expressed by the APC available in the periphery to activate T cell effector functions. However, this undesirable side effect of generalized immunosuppression is obviated by a new protocol that establishes without a lethal preconditioning component, a stable state of mixed allogeneic hemopoietic chimerism sufficient to inhibit T1D development and also induce donor-specific tolerance in NOD recipients.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants DK51090, DK46266, AI46629, and DK53006; Cancer Center Support Grant CA34196; Diabetes Endocrinology Research Center Grant DK32520; as well as by grants from the Juvenile Diabetes Research Foundation; and a fellowship to M.A.B from the Charles A. King Trust, Bank of America, Co-Trustee.
2 Address correspondence and reprint requests to Dr. David V. Serreze, The Jackson Laboratory, Bar Harbor, ME 04609. E-mail address: dave.serreze{at}jax.org
3 Abbreviations used in this paper: T1D, type 1 diabetes; BM, bone marrow; GVH, graft vs host; HVG, host vs graft; PV, Pichinde virus; SP, single positive; KLH, keyhole limpet hemocyanin; MIS, mean insulitis score.
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