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© The Rockefeller University Press, 0022-1007/1996/12/2167/ $5.00
The Journal of Experimental Medicine, Volume 184, Number 6, December 1, 1996 2167-2174

Articles

Aerosol Insulin Induces Regulatory CD8 {gamma}{delta} T Cells That Prevent Murine Insulin-dependent Diabetes

Leonard C. Harrison, Majella Dempsey-Collier, David R. Kramer, and Kazuma Takahashi

From The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville 3050, Australia

Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulindependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9–23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 {gamma}{delta} T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 {gamma}{delta} T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.

The assistance and technical advice of Julie Scott, Andrew Lew, and Margo Honeyman are gratefully acknowledged. Jacques Miller, William Heath, Grant Morahan, and Tom Kay gave constructive comments on the manuscript, and Margaret Thompson provided secretarial assistance.

The authors were supported by the National Health and Medical Research Council of Australia, by a Diabetes Interdisciplinary Research Program from the Juvenile Diabetes Foundation International, and by the Manpei Suzuki Diabetes Foundation International of Japan (K. Takahashi).

Address correspondence and reprint requests to Leonard C. Harrison, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville 3050, Australia.

1Abbreviations used in this paper: DTH, delayed-type hypersensitivity; GAD, glutamic acid decarboxylase; IDDM, insulin-dependent diabetes mellitus; NOD, nonobese diabetic (mice).


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