Insulin-Dependent Diabetes Mellitus

Early attempts to prevent IDDM typically relied on immunosuppressive drugs (cyclosporine) or drugs that indiscriminantly inhibit cell proliferation (imuran), often leading to serious side effects. Therefore, a great deal of effort has focused on selectively targeting those T cells involved in the disease process. One general approach has been to employ monoclonal antibodies specific for molecules expressed by the effector T cell population. Monoclonal antibodies specific for CD4 (Shizuru et al. 1988xImmunotherapy of the nonobese diabetic mouse; treatment with an antibody to T helper lymphocytes. Shizuru, J.A, Taylor-Edwards, C, Banks, B.A, Gregory, A.K, and Fathman, C.G. Science. 1988; 240: 659–662Crossref | PubMedSee all ReferencesShizuru et al. 1988) and CD3, a component of TCRs (Chatenoud et al. 1993xAnti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Chatenoud, L, Thervet, E, Primo, J, and Bach, J.F. Proc. Natl. Acad. Sci. USA. 1993; 91: 123–127Crossref | Scopus (456)See all ReferencesChatenoud et al. 1993), have been shown to be effective in the prevention and treatment, respectively, of diabetes in NOD mice. Similarly, prediabetic NOD mice are protected from disease when treated with antibodies that interfere with antigen recognition (anti-class II, Boitard et al. 1988xPrevention of diabetes in nonobese diabetic mice by anti- I-A monoclonal antibodies (transfer of protection by splenic T cells) . Boitard, C, Bendelac, A, Richard, M.F, Carnaud, C, and Bach, J.F. Proc. Natl. Acad. Sci. USA. 1988; 85: 9719–9723Crossref | PubMedSee all ReferencesBoitard et al. 1988; anti-TCR, Sempe et al. 1991xAnti-α/β T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice. Sempe, P, Bedossa, P, Richard, M.F, Villa, M.C, Bach, J.F, and Boitard, C. Eur. J. Immunol. 1991; 21: 1163–1169Crossref | PubMedSee all ReferencesSempe et al. 1991), cellular activation (anti-B7; Lenschow et al. 1995xDifferential effects of anti-B7-1 and anti-B7-2 monoclonal treatment on the development of diabetes in the nonobese diabetic mouse. Lenschow, D.J, Ho, S.C, Sattar, H, Rhee, L, Gray, G, Nabavi, N, Herold, K.C, and Bluestone, J.A. J. Exp. Med. 1995; 181: 1145–1155Crossref | PubMed | Scopus (528)See all ReferencesLenschow et al. 1995), and homing to the pancreas (anti–L selectin and anti-VLA-4; Yang et al. 1993xInhibition of insulitis and prevention of diabetes in nonobese diabetic mice by blocking L-selectin and very late antigen 4 adhesion receptors. Yang, X.D, Karin, N, Tisch, R, Steinman, L, and McDevitt, H.O. Proc. Natl. Acad. Sci. USA. 1993; 90: 10494–10498Crossref | PubMedSee all ReferencesYang et al. 1993). Finally, antibodies targeting cytokines associated with Th1 activity (anti-IFNγ, anti-TNFα, and anti-IL-12; Rabinovitch 1994xImmunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation. Rabinovitch, A. Diabetes. 1994; 43: 613–621Crossref | PubMedSee all ReferencesRabinovitch 1994) have been able to prevent disease in prediabetic NOD mice. In general, however, the applicability of antibodies specific for these “immune–related molecules” to human IDDM is limited by the side effects of chronic administration, such as immunogenicity, and the lack of selectivity.An alternative approach is to devise protocols in which immunomodulation can be selectively applied through the use of a specific antigen/peptide. Recently, it has been demonstrated that insulin, when adminstered prior to the onset of diabetes, can delay or prevent disease in individuals at high risk for IDDM (Keller et al. 1993xInsulin prophylaxis in individuals at high risk of type I diabetes. Keller, R.J, Eisenbarth, G.S, and Jackson, R.A. Lancet. 1993; 341: 927–928Abstract | PubMed | Scopus (261)See all ReferencesKeller et al. 1993). The precise mechanism by which protection is mediated is not known. Both metabolic and immunologic factors may contribute to the effectiveness of this form of therapy. Nevertheless, multicenter trials of subcutaneous insulin prophylaxis to individuals at high risk for developing diabetes have recently been initiated.In general, antigen-specific tolerance can be induced via two distinct processes: clonal deletion/anergy and induction of regulatory T cells. Clonal deletion/anergy has been shown to be effective in acute experimental autoimmune diseases where the inciting autoantigen/peptide is known. However, the high degree of specificity associated with this approach might be limiting in IDDM, in which the inciting autoantigen is not known, and where spreading of the autoimmune response to a number of epitopes within a single autoantigen and targeting of other autoantigens occur. Despite these reservations, administration of GAD, insulin, or HSP60 (but not carboxypeptidase H or peripherin) to NOD mice appears to result in the induction of antigen-specific regualtory T cells (Th2) that effectively suppress the disease. These regulatory T cells are thought to suppress the effects of nearby diabetogenic T cells through the antigen-stimulated secretion of IL-4, IL-10, and TGFβ. The advantage of this approach is that knowledge of the inciting β cell autoantigen (if only one such antigen truly exists) is not required. However, it is still unclear whether regimens can be devised that effectively induce a long lasting form of active suppression with no deleterious side effects in a clinical setting. For example, oral administration of antigen appears to be nontoxic, but its effects are variable and dose specific. This does not appear to be the case with systemically administered antigen. However, the possibility exists that systemic administration of antigen might have an immunizing effect and exacerbate disease.Although antigen-specific immunotherapy appears to be a promising method to prevent IDDM, it is most likely that a combination of approaches may prove to be more generally effective. Thus, active suppression by antigen-induced regulatory T cells may be enhanced in concert with antibodies targeting cytokines required for Th1 development and function. Furthermore, as additional β cell autoantigens are identified and shown to have a role in the disease process, therapy might employ a number of autoantigens to target the polyclonal population of autoreactive T cells, thereby increasing the likelihood of successful treatment.Even if safe, effective, and long lasting immunotherapies are developed, their application is a formidable challenge. Only 15% of new cases of IDDM occur in families with a previous case in the kindred. Overt diabetes develops only when β cell destruction is nearly complete, and the patient is asymptomatic for months or years until that point is reached. Immunotherapy thus must be preventive, which requires inexpensive, accurate genetic, autoantibody, and T cell screening techniques. Given the large number of islet cell autoantigens now available and the rapid progress in identifying genetic susceptibility markers, such screening techniques should soon be feasible. Hopefully, effective methods of prevention will promote widespread population screening and the application of preventive therapy.