Abstract
THE receptor–ligand pairs CD28–B7 and CD40–gp39 are essential for the initiation and amplification of T-cell-dependent immune responses1,2. CD28–B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production3–5, whereas CD40–gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation6–12. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts13–15. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bluestone, J. A. Immunity 2, 555–559 (1995).
Banchereau, J. et al. A. Rev. Immun. 12, 881–922 (1994).
Jenkins, M. K., Taylor, P. S., Norton, S. D. & Urdahl, K. B., J. Immun. 147, 2461–2466 (1991).
Schwartz, R. H. Cell 71, 1065–1068 (1992).
Boussiotis, V. A., Freeman, G. J., Gray, G., Gribben, J. & Nadler, L. M. J. exp. Med. 178, 1753–1763 (1993).
Grewal, I. S., Xu, J. & Flavell, R. A. Nature 378, 617–620 (1995).
van Essen, D., Kikutani, H. & Gray, D. Nature 378, 620–623 (1995).
Hollenbaugh, D. et al. J. exp. Med. 182, 33–40 (1995).
Armitage, R. J. et al. Nature 357, 80–82 (1992).
Cayabyab, M., Phillips, J. H. & Lanier, L. L. J. Immun. 152, 1523–1531 (1994).
Noelle, R. et al. Proc. natn. Acad. Sci. U.S.A. 89, 6550–6554 (1992).
Alderson, M. et al. J. exp. Med. 178, 669–674 (1993).
Turka, L. A. et al. Proc. natn. Acad. Sci. U.S.A. 89, 11102–11105 (1992).
Parker, D. C. et al. Proc. natn. Acad. Sci. U.S.A. 92, 9560–9564 (1995).
Larsen, C. P. et al. Transplantation 61, 4–9 (1996).
Kaye, J. & Hedrick, S. M. Nature 336, 580–583 (1988).
Sha, W. C. et al. Nature 335, 271–274 (1988).
Linsley, P. S. et al. J. exp. Med. 174, 561–569 (1991).
MacDonald, H. R. et al. Nature 332, 40–45 (1988).
Pearson, T. C. et al. Transplantation 61, 997–1004 (1996).
Larsen, C. P. et al. J. Immun. 152, 5208–5219 (1994).
Cobbold, S., Jayasuriya, A., Nash, A., Prospero, T. & Waldman, H. Nature 312, 548–551 (1984).
Mayumi, H. & Good, R. A. J. exp. Med. 169, 213–238 (1990).
Ildstad, S. T. & Sachs, D. H. Nature 307, 168–170 (1984).
Cobbold, S. P., Martin, G., Qin, S. & Waldmann, H. Nature 323, 164–166 (1986).
Qin, S. et al. Science 259, 974–977 (1993).
Corry, R. J., Winn, H. J. & Russell, P. S. Transplantation 16, 343–350 (1973).
Pereira, G. M., Miller, J. F. & Shevach, E. M. J. Immun. 144, 2109–2116 (1990).
Pearson, T., Darby, C. R., Bushell, A. R., Morris, P. J. & Wood, K. J. Transplantation 55, 361–367 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Larsen, C., Elwood, E., Alexander, D. et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381, 434–438 (1996). https://doi.org/10.1038/381434a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/381434a0
This article is cited by
-
Activation and regulation of alloreactive T cell immunity in solid organ transplantation
Nature Reviews Nephrology (2022)
-
Donor bone-marrow CXCR4+ Foxp3+ T-regulatory cells are essential for costimulation blockade-induced long-term survival of murine limb transplants
Scientific Reports (2020)
-
Targeting co-stimulatory molecules in autoimmune disease
Nature Reviews Drug Discovery (2020)
-
Costimulation Blockade in Kidney Transplant Recipients
Drugs (2020)
-
CD154/CD40-Interaktion
Der Nephrologe (2017)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
