Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes - PubMed (original) (raw)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes

F Lühder et al. J Exp Med. 1998.

Abstract

Evidence has been accumulating that shows that insulin-dependent diabetes is subject to immunoregulation. To determine whether cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is involved, we injected anti-CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would normally become diabetic, anti-CTLA-4 induced diabetes rapidly and essentially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltrate in the pancreatic islets. These effects were only observed if anti-CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engagement is permitted, invasion of the islets occurs, but remains quite innocuous for months, if not, insulitis is much more aggressive, and diabetes quickly ensues.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Treatment with anti–CTLA-4 mAb provokes a rapid onset of diabetes. BDC2.5/NOD mice were injected intraperitoneally with anti–CTLA-4, anti-CD28, or control mAb at 9, 12, and 15 d of age (total dose: 250–300 μg).

Figure 2

Figure 2

Anti–CTLA-4 treatment works only when first administered before the initiation of insulitis. (A) BDC2.5/NOD mice were treated with anti–CTLA-4 mAb using a variety of protocols. All received a total dose of 250–300 μg, except those injected only on day 12, which got 200 μg. The day on which the mAb was first administered is indicated. Carrots, individual injections; stippling, the presence of anti–CTLA-4; solid black, the cumulative frequency of diabetes. The numbers to the right represent the final frequency of diabetics. All experiments included anti-CD28 and/or irrelevant mAb controls. In several experiments, paired littermates received earlier (before 12 d) or later (after 17 d) injections. (B) Groups of BDC2.5/NOD mice were killed at different ages, and insulitis quantitated. Each bar represents the average proportion of infiltrated islets (groups of 5–12 mice). The horizontal scale (days of age) matches that of A.

Figure 3

Figure 3

Treatment with anti–CTLA-4 does not provoke global T cell activation but enhances the aggressiveness of insulitis. (A) Lymphocytes from the spleen, mesenteric lymph nodes, or pancreas of 17-d-old BDC2.5/NOD mice, after injection with either control mAb (left) or anti–CTLA-4 (right) on day 12, were stained for CD4, CD8, and CD69 or CD62L. The profiles depict cells gated for CD4 positivity. The bars indicate positive staining. (B) Representative pancreas sections from BDC2.5/NOD transgenics treated with control mAb (left) or anti–CTLA-4 (right). (Top) Injections on days 2, 5, and 8 and pancreas removal on day 11. (Bottom) Injections on days 9, 12, and 15 and pancreas removal on day 17.

Figure 3

Figure 3

Treatment with anti–CTLA-4 does not provoke global T cell activation but enhances the aggressiveness of insulitis. (A) Lymphocytes from the spleen, mesenteric lymph nodes, or pancreas of 17-d-old BDC2.5/NOD mice, after injection with either control mAb (left) or anti–CTLA-4 (right) on day 12, were stained for CD4, CD8, and CD69 or CD62L. The profiles depict cells gated for CD4 positivity. The bars indicate positive staining. (B) Representative pancreas sections from BDC2.5/NOD transgenics treated with control mAb (left) or anti–CTLA-4 (right). (Top) Injections on days 2, 5, and 8 and pancreas removal on day 11. (Bottom) Injections on days 9, 12, and 15 and pancreas removal on day 17.

Similar articles

Cited by

References

    1. Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994;15:516–542. - PubMed
    1. Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell. 1996;85:291–297. - PubMed
    1. Katz JD, Wang B, Haskins K, Benoist C, Mathis D. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993;74:1089–1100. - PubMed
    1. Haskins K, McDuffie M. Acceleration of diabetes in young NOD mice with a CD4+islet-specific T-cell clone. Science. 1990;249:1433–1436. - PubMed
    1. Gonzalez A, Katz JD, Mattei MG, Kikutani H, Benoist C, Mathis D. Genetic control of diabetes progression. Immunity. 1997;7:873–883. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources