Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection
Joel Trambley, … , Thomas C. Pearson, Christian P. Larsen
Joel Trambley, … , Thomas C. Pearson, Christian P. Larsen
Published December 15, 1999
Citation Information: J Clin Invest. 1999;104(12):1715-1722. https://doi.org/10.1172/JCI8082.
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Article

Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Abstract

Simultaneous blockade of the CD40 and CD28 costimulatory pathways is an effective treatment strategy to promote allograft acceptance but does not lead to indefinite allograft survival. The immune mechanisms responsible for costimulation-independent rejection are not defined. Here we have studied the rejection responses of murine C57BL/6 recipients, which we show to be relatively resistant to inhibition by combined CD40/CD28 blockade. We demonstrate that asialo GM1+ CD8+ cells play a critical role in this costimulation blockade–resistant rejection. These results provide new insights into the costimulatory requirements for T-cell subsets and demonstrate for the first time that combined blockade of the CD40 and CD28 pathways does not adequately inhibit CD8-mediated skin allograft rejection. Furthermore, we provide evidence that asialo GM1 is a potentially important therapeutic target for CD8-dependent immune responses.

Authors

Joel Trambley, Adam W. Bingaman, Angello Lin, Eric T. Elwood, Seung-Yeun Waitze, Jongwon Ha, Megan M. Durham, Matthias Corbascio, Shannon R. Cowan, Thomas C. Pearson, Christian P. Larsen

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Anti–asialo GM1 delays skin allograft rejection mediated by CD8+ T cells...
Anti–asialo GM1 delays skin allograft rejection mediated by CD8+ T cells. (a and b) B6 Rag1–/– recipients were reconstituted with 107 B6 CD4+ or CD8+ T cells and transplanted with Balb/c skin allografts 2 days later. (a) Recipients reconstituted with B6 CD4+ T cells promptly rejected Balb/c skin allografts when treated with rabbit Ig (MST 12 days; n = 5) or anti–asialo GM1 (MST 13 days; n = 5). (b) Recipients reconstituted with CD8+ T cells treated with rabbit Ig (MST 11 days; n = 5) promptly rejected Balb/c skin allografts. Recipients reconstituted with CD8 cells treated with anti–asialo GM1 had significantly prolonged allograft survival (MST 37 days; n = 4; P < 0.02). (c) B6 B2-microglobulin–/– promptly rejected Balb/c skin allografts when treated with rabbit IgG (MST 10 days; n = 5) or anti–asialo GM1 (MST 10 days; n = 7). (d) Balb/c skin graft survival was significantly prolonged in B6 class II–/– recipients treated with anti–asialo GM1 (MST 26 days; n = 7) compared with recipients treated with rabbit Ig (MST 12 days; n = 5; P < 0.01). Treatment of B6 class II–/– recipients with anti-NK1.1 did not significantly prolong graft survival (MST 13 days; n = 7).