| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Dumont-University of California Transplant Center, University of California School of Medicine, Los Angeles, CA 90095;
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205; and
Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Although the CD154-CD40 T cell costimulation pathway has been shown to mediate alloimmune responses in normal recipients, little is known about its role in sensitized hosts. In this work, by using novel models of cardiac allograft rejection in skin-sensitized CD154- and CD40-deficient mice, we reaffirm the key role of CD154-CD40 signaling in host sensitization to alloantigen in vivo. First, we identified CD8+ T cells as principal effectors in executing accelerated rejection in our model. Disruption of CD154-CD40 signaling in recipients at the T cell side (CD154-deficient) but not at the APC side (CD40-deficient) abrogated accelerated (<2 days) rejection and resulted in long-term (>100 days) graft survival. This suggests that the CD154-dependent mechanism in host CD8+ T cell sensitization operates via the direct Ag presentation. Then, in comparative studies of alloimmune responses in CD154-deficient and wild-type recipients, we showed that, although alloreactive B cell responses were inhibited, alloreactive T cell responses were down-regulated selectively in the CD8+ T cell compartment, leaving CD4+ T cells largely unaffected. This unique alteration in host alloreactivity, seen not only in peripheral lymphocytes but also in allograft infiltrate, may represent the key mechanism by which disruption of CD154-CD40 signaling prevents sensitization to alloantigen in vivo and leads to long-term allograft survival.
This article has been cited by other articles:
|
|
 |
|
  H. Xu, Y. Huang, P. M. Chilton, L.-R. Hussain, M. K. Tanner, J. Yan, and S. T. Ildstad Strategic Nonmyeloablative Conditioning: CD154:CD40 Costimulatory Blockade at Primary Bone Marrow Transplantation Promotes Engraftment for Secondary Bone Marrow Transplantation after Engraftment Failure J. Immunol., November 1, 2008; 181(9): 6616 - 6624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wu, Y. Wang, F. Gao, X. Shen, Y. Zhai, and J. W. Kupiec-Weglinski Critical Role of CD4 Help in CD154 Blockade-Resistant Memory CD8 T Cell Activation and Allograft Rejection in Sensitized Recipients J. Immunol., July 15, 2008; 181(2): 1096 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, Y. Wang, Z. Wu, and J. W. Kupiec-Weglinski Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help J. Immunol., October 1, 2007; 179(7): 4529 - 4534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Methe, A. Groothuis, M. H. Sayegh, and E. R. Edelman Matrix adherence of endothelial cells attenuates immune reactivity: induction of hyporesponsiveness in allo- and xenogeneic models FASEB J, May 1, 2007; 21(7): 1515 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Methe and E. R. Edelman Cell-Matrix Contact Prevents Recognition and Damage of Endothelial Cells in States of Heightened Immunity Circulation, July 4, 2006; 114(1_suppl): I-233 - I-238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, L. Meng, F. Gao, Y. Wang, R. W. Busuttil, and J. W. Kupiec-Weglinski CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent J. Immunol., May 15, 2006; 176(10): 5988 - 5994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Lunsford, M. A. Koester, A. M. Eiring, P. H. Horne, D. Gao, and G. L. Bumgardner Targeting LFA-1 and CD154 Suppresses the In Vivo Activation and Development of Cytolytic (CD4-Independent) CD8+ T Cells J. Immunol., December 15, 2005; 175(12): 7855 - 7866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ito, T. Ueno, M. R. Clarkson, X. Yuan, M. M. Jurewicz, H. Yagita, M. Azuma, A. H. Sharpe, H. Auchincloss Jr, M. H. Sayegh, et al. Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo J. Immunol., June 1, 2005; 174(11): 6648 - 6656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Ferrant, C. D. Benjamin, A. H. Cutler, S. L. Kalled, Y.-M. Hsu, E. A. Garber, D. M. Hess, R. I. Shapiro, N. S. Kenyon, D. M. Harlan, et al. The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge Int. Immunol., November 1, 2004; 16(11): 1583 - 1594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Quemeneur, L. Beloeil, M.-C. Michallet, G. Angelov, M. Tomkowiak, J.-P. Revillard, and J. Marvel Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells J. Immunol., October 15, 2004; 173(8): 4945 - 4952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Nagelkerken, I. Haspels, W. van Rijs, B. Blauw, J. L. Ferrant, D. M. Hess, E. A. Garber, F. R. Taylor, and L. C. Burkly FcR Interactions Do Not Play a Major Role in Inhibition of Experimental Autoimmune Encephalomyelitis by Anti-CD154 Monoclonal Antibodies J. Immunol., July 15, 2004; 173(2): 993 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. El-Sawy, M. Miura, and R. Fairchild Early T Cell Response to Allografts Occuring Prior to Alloantigen Priming Up-Regulates Innate-Mediated Inflammation and Graft Necrosis Am. J. Pathol., July 1, 2004; 165(1): 147 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Abdi, T. K. Means, T. Ito, R. N. Smith, N. Najafian, M. Jurewicz, V. Tchipachvili, I. Charo, H. Auchincloss Jr., M. H. Sayegh, et al. Differential Role of CCR2 in Islet and Heart Allograft Rejection: Tissue Specificity of Chemokine/Chemokine Receptor Function In Vivo J. Immunol., January 15, 2004; 172(2): 767 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, L. Meng, R. W. Busuttil, M. H. Sayegh, and J. W. Kupiec-Weglinski Activation of Alloreactive CD8+ T Cells Operates Via CD4-Dependent and CD4-Independent Mechanisms and Is CD154 Blockade Sensitive J. Immunol., March 15, 2003; 170(6): 3024 - 3028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, L. Meng, F. Gao, R. W. Busuttil, and J. W. Kupiec-Weglinski Allograft Rejection by Primed/Memory CD8+ T Cells Is CD154 Blockade Resistant: Therapeutic Implications for Sensitized Transplant Recipients J. Immunol., October 15, 2002; 169(8): 4667 - 4673. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
