Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses

Richard S. Lee, Kazuhiko Yamada, Karl L. Womer, Edmund P. Pillsbury, Kenneth S. Allison, Ariane E. Marolewski, Dong Geng, Aron D. Thall, J. Scott Arn, David H. Sachs, Mohamed H. Sayegh, Joren C. Madsen

Research output: Contribution to journalArticle

Abstract

Despite increasing use of swine in transplantation research, the ability to block costimulation of allogeneic T cell responses has not been demonstrated in swine, and the effects of costimulatory blockade on xenogeneic human anti-porcine T cell responses are also not clear. We have compared the in vitro effects of anti-human CD154 mAb and human CTLA4IgG4 on allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses. Both anti-CD154 mAb and CTLA4IgG4 cross-reacted or pig cells. While anti-CD154 mAb and CTLA4IgG4 both inhibited the primary allogeneic pig MLRs, CTLA4IgG4 (7.88 μg/ml was considerably more inhibitory than anti-CD154 mAb (100 μg/ml) at optimal doses. Anti-CD154 mAb inhibited the production of IFN-γ by 75%, but did not inhibit IL-10 production, while CTLA4IgG4 completely inhibited the production of both IFN-γ and IL-10. In secondary allogeneic pig MLRs, CTLA4IgG4, but not anti-CD154 mAb, induced Ag-specific T cell anergy. CTLAIgG4 completely blocked the indirect pathway of allorecognition, while anti-CD154 mAb blocked the indirect response by approximately 50%. The generation of porcine CTLs was inhibited by CTLA4IgG4, but not by anti-CD154 mAb. Human anti-porcine xenogeneic MLRs were blocked by CTLA4IgG4, but only minimally by anti-CD154 mAb. Finally, CTLA4IgG4 prevented secondary xenogeneic human anti-porcine T cell responses. These data indicate that blockade of the B7-CD28 pathway was more effective than blockade of the CD40-CD154 pathway in inhibiting allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses in vitro. These findings have implications for inhibiting cell-mediated immune responses in pig-to-human xenotransplantation.

Original languageEnglish (US)
Pages (from-to)3434-3444
Number of pages11
JournalJournal of Immunology
Volume164
Issue number6
StatePublished - Mar 15 2000
Externally publishedYes

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Swine
T-Lymphocytes
Thomsen-Friedenreich antibodies
Interleukin-10
Heterologous Transplantation
Transplantation

ASJC Scopus subject areas

  • Immunology

Cite this

Lee, R. S., Yamada, K., Womer, K. L., Pillsbury, E. P., Allison, K. S., Marolewski, A. E., ... Madsen, J. C. (2000). Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses. Journal of Immunology, 164(6), 3434-3444.

Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses. / Lee, Richard S.; Yamada, Kazuhiko; Womer, Karl L.; Pillsbury, Edmund P.; Allison, Kenneth S.; Marolewski, Ariane E.; Geng, Dong; Thall, Aron D.; Arn, J. Scott; Sachs, David H.; Sayegh, Mohamed H.; Madsen, Joren C.

In: Journal of Immunology, Vol. 164, No. 6, 15.03.2000, p. 3434-3444.

Research output: Contribution to journalArticle

Lee, RS, Yamada, K, Womer, KL, Pillsbury, EP, Allison, KS, Marolewski, AE, Geng, D, Thall, AD, Arn, JS, Sachs, DH, Sayegh, MH & Madsen, JC 2000, 'Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses', Journal of Immunology, vol. 164, no. 6, pp. 3434-3444.
Lee RS, Yamada K, Womer KL, Pillsbury EP, Allison KS, Marolewski AE et al. Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses. Journal of Immunology. 2000 Mar 15;164(6):3434-3444.
Lee, Richard S. ; Yamada, Kazuhiko ; Womer, Karl L. ; Pillsbury, Edmund P. ; Allison, Kenneth S. ; Marolewski, Ariane E. ; Geng, Dong ; Thall, Aron D. ; Arn, J. Scott ; Sachs, David H. ; Sayegh, Mohamed H. ; Madsen, Joren C. / Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses. In: Journal of Immunology. 2000 ; Vol. 164, No. 6. pp. 3434-3444.
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abstract = "Despite increasing use of swine in transplantation research, the ability to block costimulation of allogeneic T cell responses has not been demonstrated in swine, and the effects of costimulatory blockade on xenogeneic human anti-porcine T cell responses are also not clear. We have compared the in vitro effects of anti-human CD154 mAb and human CTLA4IgG4 on allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses. Both anti-CD154 mAb and CTLA4IgG4 cross-reacted or pig cells. While anti-CD154 mAb and CTLA4IgG4 both inhibited the primary allogeneic pig MLRs, CTLA4IgG4 (7.88 μg/ml was considerably more inhibitory than anti-CD154 mAb (100 μg/ml) at optimal doses. Anti-CD154 mAb inhibited the production of IFN-γ by 75{\%}, but did not inhibit IL-10 production, while CTLA4IgG4 completely inhibited the production of both IFN-γ and IL-10. In secondary allogeneic pig MLRs, CTLA4IgG4, but not anti-CD154 mAb, induced Ag-specific T cell anergy. CTLAIgG4 completely blocked the indirect pathway of allorecognition, while anti-CD154 mAb blocked the indirect response by approximately 50{\%}. The generation of porcine CTLs was inhibited by CTLA4IgG4, but not by anti-CD154 mAb. Human anti-porcine xenogeneic MLRs were blocked by CTLA4IgG4, but only minimally by anti-CD154 mAb. Finally, CTLA4IgG4 prevented secondary xenogeneic human anti-porcine T cell responses. These data indicate that blockade of the B7-CD28 pathway was more effective than blockade of the CD40-CD154 pathway in inhibiting allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses in vitro. These findings have implications for inhibiting cell-mediated immune responses in pig-to-human xenotransplantation.",
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AU - Lee, Richard S.

AU - Yamada, Kazuhiko

AU - Womer, Karl L.

AU - Pillsbury, Edmund P.

AU - Allison, Kenneth S.

AU - Marolewski, Ariane E.

AU - Geng, Dong

AU - Thall, Aron D.

AU - Arn, J. Scott

AU - Sachs, David H.

AU - Sayegh, Mohamed H.

AU - Madsen, Joren C.

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N2 - Despite increasing use of swine in transplantation research, the ability to block costimulation of allogeneic T cell responses has not been demonstrated in swine, and the effects of costimulatory blockade on xenogeneic human anti-porcine T cell responses are also not clear. We have compared the in vitro effects of anti-human CD154 mAb and human CTLA4IgG4 on allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses. Both anti-CD154 mAb and CTLA4IgG4 cross-reacted or pig cells. While anti-CD154 mAb and CTLA4IgG4 both inhibited the primary allogeneic pig MLRs, CTLA4IgG4 (7.88 μg/ml was considerably more inhibitory than anti-CD154 mAb (100 μg/ml) at optimal doses. Anti-CD154 mAb inhibited the production of IFN-γ by 75%, but did not inhibit IL-10 production, while CTLA4IgG4 completely inhibited the production of both IFN-γ and IL-10. In secondary allogeneic pig MLRs, CTLA4IgG4, but not anti-CD154 mAb, induced Ag-specific T cell anergy. CTLAIgG4 completely blocked the indirect pathway of allorecognition, while anti-CD154 mAb blocked the indirect response by approximately 50%. The generation of porcine CTLs was inhibited by CTLA4IgG4, but not by anti-CD154 mAb. Human anti-porcine xenogeneic MLRs were blocked by CTLA4IgG4, but only minimally by anti-CD154 mAb. Finally, CTLA4IgG4 prevented secondary xenogeneic human anti-porcine T cell responses. These data indicate that blockade of the B7-CD28 pathway was more effective than blockade of the CD40-CD154 pathway in inhibiting allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses in vitro. These findings have implications for inhibiting cell-mediated immune responses in pig-to-human xenotransplantation.

AB - Despite increasing use of swine in transplantation research, the ability to block costimulation of allogeneic T cell responses has not been demonstrated in swine, and the effects of costimulatory blockade on xenogeneic human anti-porcine T cell responses are also not clear. We have compared the in vitro effects of anti-human CD154 mAb and human CTLA4IgG4 on allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses. Both anti-CD154 mAb and CTLA4IgG4 cross-reacted or pig cells. While anti-CD154 mAb and CTLA4IgG4 both inhibited the primary allogeneic pig MLRs, CTLA4IgG4 (7.88 μg/ml was considerably more inhibitory than anti-CD154 mAb (100 μg/ml) at optimal doses. Anti-CD154 mAb inhibited the production of IFN-γ by 75%, but did not inhibit IL-10 production, while CTLA4IgG4 completely inhibited the production of both IFN-γ and IL-10. In secondary allogeneic pig MLRs, CTLA4IgG4, but not anti-CD154 mAb, induced Ag-specific T cell anergy. CTLAIgG4 completely blocked the indirect pathway of allorecognition, while anti-CD154 mAb blocked the indirect response by approximately 50%. The generation of porcine CTLs was inhibited by CTLA4IgG4, but not by anti-CD154 mAb. Human anti-porcine xenogeneic MLRs were blocked by CTLA4IgG4, but only minimally by anti-CD154 mAb. Finally, CTLA4IgG4 prevented secondary xenogeneic human anti-porcine T cell responses. These data indicate that blockade of the B7-CD28 pathway was more effective than blockade of the CD40-CD154 pathway in inhibiting allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses in vitro. These findings have implications for inhibiting cell-mediated immune responses in pig-to-human xenotransplantation.

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