| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-University of California Transplant Center, University of California School of Medicine, Los Angeles, CA 90095
We have shown that CD8+ CTLs are the key mediators of accelerated rejection, and that CD8+ T cells represent the prime targets of CD154 blockade in sensitized mouse recipients of cardiac allografts. However, the current protocols require CD154 blockade at the time of sensitization, whereas delayed treatment fails to affect graft rejection in sensitized recipients. To elucidate the mechanisms of costimulation blockade-resistant rejection and to improve the efficacy of CD154-targeted therapy, we found that alloreactive CD8+ T cells were activated despite the CD154 blockade in sensitized hosts. Comparative CD8 T cell activation study in naive vs primed hosts has shown that although both naive and primed/memory CD8+ T cells relied on the CD28 costimulation for their activation, only naive, not primed/memory, CD8+ T cells depend on CD154 signaling to differentiate into CTL effector cells. Adjunctive therapy was designed accordingly to deplete primed/memory CD8+ T cells before the CD154 blockade. Indeed, unlike anti-CD154 monotherapy, transient depletion of CD8+ T cells around the time of cardiac engraftment significantly improved the efficacy of delayed CD154 blockade in sensitized hosts. Hence, this report provides evidence for 1) differential requirement of CD154 costimulation signals for naive vs primed/memory CD8+ T cells, and 2) successful treatment of clinically relevant sensitized recipients to achieve stable long term graft acceptance.
This article has been cited by other articles:
|
|
 |
|
  X. Yuan, M. J. Ansari, F. D'Addio, J. Paez-Cortez, I. Schmitt, M. Donnarumma, O. Boenisch, X. Zhao, J. Popoola, M. R. Clarkson, et al. Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells PNAS, June 30, 2009; 106(26): 10734 - 10739. [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]
|
|
|
|
 |
|
 H. Xu, J. Yan, Y. Huang, P. M. Chilton, C. Ding, C. L. Schanie, L. Wang, and S. T. Ildstad Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization Blood, March 15, 2008; 111(6): 3266 - 3275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wang, H. Dai, N. Wan, Y. Moore, and Z. Dai The Role for Monocyte Chemoattractant Protein-1 in the Generation and Function of Memory CD8+ T Cells J. Immunol., March 1, 2008; 180(5): 2886 - 2893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Wan, H. Dai, T. Wang, Y. Moore, X. X. Zheng, and Z. Dai Bystander Central Memory but Not Effector Memory CD8+ T Cells Suppress Allograft Rejection J. Immunol., January 1, 2008; 180(1): 113 - 121. [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]
|
|
|
|
 |
|
 A. Valujskikh and X. C. Li Frontiers in Nephrology: T Cell Memory as a Barrier to Transplant Tolerance J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2252 - 2261. [Full Text] [PDF]
|
|
|
|
|
|
L. K. Selin and M. A. Brehm Frontiers in Nephrology: Heterologous Immunity, T Cell Cross-Reactivity, and Alloreactivity J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2268 - 2277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Liu, H. Dai, N. Wan, T. Wang, S. Bertera, M. Trucco, and Z. Dai Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism J. Immunol., April 1, 2007; 178(7): 4260 - 4266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, P. M. Chilton, M. K. Tanner, Y. Huang, C. L. Schanie, M. Dy-Liacco, J. Yan, and S. T. Ildstad Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients Blood, November 15, 2006; 108(10): 3611 - 3619. [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]
|
|
|
|
|
|
D. C. Neujahr, C. Chen, X. Huang, J. F. Markmann, S. Cobbold, H. Waldmann, M. H. Sayegh, W. W. Hancock, and L. A. Turka Accelerated Memory Cell Homeostasis during T Cell Depletion and Approaches to Overcome It. J. Immunol., April 15, 2006; 176(8): 4632 - 4639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Koehn, S. Gangappa, J. D. Miller, R. Ahmed, and C. P. Larsen Patients, pathogens, and protective immunity: the relevance of virus-induced alloreactivity in transplantation. J. Immunol., March 1, 2006; 176(5): 2691 - 2696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Vu, M. R. Clarkson, H. Yagita, L. A. Turka, M. H. Sayegh, and X. C. Li Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection J. Immunol., February 1, 2006; 176(3): 1394 - 1401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. W. Nasr, Y. Wang, G. Gao, S. Deng, L. Diggs, D. M. Rothstein, G. Tellides, F. G. Lakkis, and Z. Dai Testicular Immune Privilege Promotes Transplantation Tolerance by Altering the Balance between Memory and Regulatory T Cells J. Immunol., May 15, 2005; 174(10): 6161 - 6168. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
G. Chalasani, Q. Li, B. T. Konieczny, L. Smith-Diggs, B. Wrobel, Z. Dai, D. L. Perkins, F. K. Baddoura, and F. G. Lakkis The Allograft Defines the Type of Rejection (Acute versus Chronic) in the Face of an Established Effector Immune Response J. Immunol., June 15, 2004; 172(12): 7813 - 7820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, P. S. Heeger, and A. Valujskikh In Vivo Helper Functions of Alloreactive Memory CD4+ T Cells Remain Intact Despite Donor-Specific Transfusion and Anti-CD40 Ligand Therapy J. Immunol., May 1, 2004; 172(9): 5456 - 5466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Demirci, F. Amanullah, R. Kewalaramani, H. Yagita, T. B. Strom, M. H. Sayegh, and X. C. Li Critical Role of OX40 in CD28 and CD154-Independent Rejection J. Immunol., February 1, 2004; 172(3): 1691 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Lakkis and M. H. Sayegh Memory T Cells: A Hurdle to Immunologic Tolerance J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2402 - 2410. [Full Text] [PDF]
|
|
|
|
|
|
M. A. Brehm, T. G. Markees, K. A. Daniels, D. L. Greiner, A. A. Rossini, and R. M. Welsh Direct Visualization of Cross-Reactive Effector and Memory Allo-Specific CD8 T Cells Generated in Response to Viral Infections J. Immunol., April 15, 2003; 170(8): 4077 - 4086. [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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
