Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 May 1;181(5):1869–1874. doi: 10.1084/jem.181.5.1869

CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2

PMCID: PMC2192009  PMID: 7536798

Abstract

Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig- treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig- treated animals was associated with increased staining for the Th2- related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig- treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig- treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.

Full Text

The Full Text of this article is available as a PDF (1.9 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Austyn J. M., Hankins D. F., Larsen C. P., Morris P. J., Rao A. S., Roake J. A. Isolation and characterization of dendritic cells from mouse heart and kidney. J Immunol. 1994 Mar 1;152(5):2401–2410. [PubMed] [Google Scholar]
  2. Boussiotis V. A., Freeman G. J., Gribben J. G., Daley J., Gray G., Nadler L. M. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11059–11063. doi: 10.1073/pnas.90.23.11059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Croft M., Swain S. L. B cell response to T helper cell subsets. II. Both the stage of T cell differentiation and the cytokines secreted determine the extent and nature of helper activity. J Immunol. 1991 Dec 1;147(11):3679–3689. [PubMed] [Google Scholar]
  4. Hancock W. W., Khoury S. J., Carpenter C. B., Sayegh M. H. Differential effects of oral versus intrathymic administration of polymorphic major histocompatibility complex class II peptides on mononuclear and endothelial cell activation and cytokine expression during a delayed-type hypersensitivity response. Am J Pathol. 1994 Jun;144(6):1149–1158. [PMC free article] [PubMed] [Google Scholar]
  5. Khoury S. J., Hancock W. W., Weiner H. L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med. 1992 Nov 1;176(5):1355–1364. doi: 10.1084/jem.176.5.1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Khoury S. J., Sayegh M. H., Hancock W. W., Gallon L., Carpenter C. B., Weiner H. L. Acquired tolerance to experimental autoimmune encephalomyelitis by intrathymic injection of myelin basic protein or its major encephalitogenic peptide. J Exp Med. 1993 Aug 1;178(2):559–566. doi: 10.1084/jem.178.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kupiec-Weglinski J. W., Wasowska B., Papp I., Schmidbauer G., Sayegh M. H., Baldwin W. M., 3rd, Wieder K. J., Hancock W. W. CD4 mAb therapy modulates alloantibody production and intracardiac graft deposition in association with selective inhibition of Th1 lymphokines. J Immunol. 1993 Nov 1;151(9):5053–5061. [PubMed] [Google Scholar]
  8. Lenschow D. J., Zeng Y., Thistlethwaite J. R., Montag A., Brady W., Gibson M. G., Linsley P. S., Bluestone J. A. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992 Aug 7;257(5071):789–792. doi: 10.1126/science.1323143. [DOI] [PubMed] [Google Scholar]
  9. Lin H., Bolling S. F., Linsley P. S., Wei R. Q., Gordon D., Thompson C. B., Turka L. A. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med. 1993 Nov 1;178(5):1801–1806. doi: 10.1084/jem.178.5.1801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Linsley P. S., Ledbetter J. A. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212. doi: 10.1146/annurev.iy.11.040193.001203. [DOI] [PubMed] [Google Scholar]
  11. Linsley P. S., Wallace P. M., Johnson J., Gibson M. G., Greene J. L., Ledbetter J. A., Singh C., Tepper M. A. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992 Aug 7;257(5071):792–795. doi: 10.1126/science.1496399. [DOI] [PubMed] [Google Scholar]
  12. Lu P., Zhou X., Chen S. J., Moorman M., Morris S. C., Finkelman F. D., Linsley P., Urban J. F., Gause W. C. CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite. J Exp Med. 1994 Aug 1;180(2):693–698. doi: 10.1084/jem.180.2.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McArthur J. G., Raulet D. H. CD28-induced costimulation of T helper type 2 cells mediated by induction of responsiveness to interleukin 4. J Exp Med. 1993 Nov 1;178(5):1645–1653. doi: 10.1084/jem.178.5.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mosmann T. R., Coffman R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–147. doi: 10.1016/s0065-2776(08)60652-5. [DOI] [PubMed] [Google Scholar]
  15. Pearson T. C., Alexander D. Z., Winn K. J., Linsley P. S., Lowry R. P., Larsen C. P. Transplantation tolerance induced by CTLA4-Ig. Transplantation. 1994 Jun 27;57(12):1701–1706. [PubMed] [Google Scholar]
  16. Sayegh M. H., Perico N., Gallon L., Imberti O., Hancock W. W., Remuzzi G., Carpenter C. B. Mechanisms of acquired thymic unresponsiveness to renal allografts. Thymic recognition of immunodominant allo-MHC peptides induces peripheral T cell anergy. Transplantation. 1994 Jul 27;58(2):125–132. [PubMed] [Google Scholar]
  17. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  18. Seder R. A., Germain R. N., Linsley P. S., Paul W. E. CD28-mediated costimulation of interleukin 2 (IL-2) production plays a critical role in T cell priming for IL-4 and interferon gamma production. J Exp Med. 1994 Jan 1;179(1):299–304. doi: 10.1084/jem.179.1.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Snijdewint F. G., Kaliński P., Wierenga E. A., Bos J. D., Kapsenberg M. L. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol. 1993 Jun 15;150(12):5321–5329. [PubMed] [Google Scholar]
  20. Takeuchi T., Lowry R. P., Konieczny B. Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance. Transplantation. 1992 Jun;53(6):1281–1294. [PubMed] [Google Scholar]
  21. Tan P., Anasetti C., Hansen J. A., Melrose J., Brunvand M., Bradshaw J., Ledbetter J. A., Linsley P. S. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med. 1993 Jan 1;177(1):165–173. doi: 10.1084/jem.177.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Turka L. A., Linsley P. S., Lin H., Brady W., Leiden J. M., Wei R. Q., Gibson M. L., Zheng X. G., Myrdal S., Gordon D. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11102–11105. doi: 10.1073/pnas.89.22.11102. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES