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.
Figures
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
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
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
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
- Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells.
Luhder F, Chambers C, Allison JP, Benoist C, Mathis D. Luhder F, et al. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12204-9. doi: 10.1073/pnas.200348397. Proc Natl Acad Sci U S A. 2000. PMID: 11035773 Free PMC article. - Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.
Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, Nabavi N, Herold KC, Bluestone JA. Lenschow DJ, et al. J Exp Med. 1995 Mar 1;181(3):1145-55. doi: 10.1084/jem.181.3.1145. J Exp Med. 1995. PMID: 7532678 Free PMC article. - Role of the B7-CD28/CTLA-4 pathway in autoimmune disease.
Chang TT, Kuchroo VK, Sharpe AH. Chang TT, et al. Curr Dir Autoimmun. 2002;5:113-30. doi: 10.1159/000060550. Curr Dir Autoimmun. 2002. PMID: 11826754 Review. No abstract available. - Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.
Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, Damle NK. Linsley PS, et al. J Exp Med. 1992 Dec 1;176(6):1595-604. doi: 10.1084/jem.176.6.1595. J Exp Med. 1992. PMID: 1334116 Free PMC article. - Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation.
Salomon B, Bluestone JA. Salomon B, et al. Annu Rev Immunol. 2001;19:225-52. doi: 10.1146/annurev.immunol.19.1.225. Annu Rev Immunol. 2001. PMID: 11244036 Review.
Cited by
- Stocking the toolbox-Using preclinical models to understand the development and treatment of immune checkpoint inhibitor-induced immune-related adverse events.
Cina ML, Venegas J, Young A. Cina ML, et al. Immunol Rev. 2023 Sep;318(1):110-137. doi: 10.1111/imr.13250. Epub 2023 Aug 10. Immunol Rev. 2023. PMID: 37565407 Free PMC article. Review. - Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases.
Ibis B, Aliazis K, Cao C, Yenyuwadee S, Boussiotis VA. Ibis B, et al. Front Immunol. 2023 Jun 5;14:1197364. doi: 10.3389/fimmu.2023.1197364. eCollection 2023. Front Immunol. 2023. PMID: 37342323 Free PMC article. Review. - Metastatic lymph node targeted CTLA4 blockade: a potent intervention for local and distant metastases with minimal ICI-induced pneumonia.
Mishra R, Sukhbaatar A, Mori S, Kodama T. Mishra R, et al. J Exp Clin Cancer Res. 2023 Jun 1;42(1):132. doi: 10.1186/s13046-023-02645-w. J Exp Clin Cancer Res. 2023. PMID: 37259163 Free PMC article. - Autoimmunity: A New Focus on Nasal Polyps.
Huang J, Xu Y. Huang J, et al. Int J Mol Sci. 2023 May 8;24(9):8444. doi: 10.3390/ijms24098444. Int J Mol Sci. 2023. PMID: 37176151 Free PMC article. Review. - Understanding the Mechanism of Diabetes Mellitus in a LRBA-Deficient Patient.
Hawari I, Ericsson J, Kabeer BSA, Chaussabel D, Alsulaiti A, Sharari SA, Maccalli C, Khan FA, Hussain K. Hawari I, et al. Biology (Basel). 2022 Apr 18;11(4):612. doi: 10.3390/biology11040612. Biology (Basel). 2022. PMID: 35453810 Free PMC article.
References
- Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994;15:516–542. - PubMed
- Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell. 1996;85:291–297. - PubMed
- 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
- 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
- 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
Full Text Sources
Other Literature Sources
Medical