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Critical Role of CD4 Help in CD154 Blockade-Resistant Memory CD8 T Cell Activation and Allograft Rejection in Sensitized Recipients¹

Zheng Wu^2,*, Yue Wang^*, Feng Gao, Xiuda Shen, Yuan Zhai^* and Jerzy W. Kupiec-Weglinski^3,*,

^* Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-University of California Transplant Center and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

Allograft rejection in sensitized recipients remains the major problem in clinical organ transplantation. We have developed a donor-type skin-sensitized mouse cardiac allograft model (BALB/cC57BL/6) in which both rejection (<5 days) and alloreactive CD8 activation are resistant to CD154 blockade. First, we attempted to elucidate why CD154 blockade fails to protect cardiac grafts in sensitized recipients. The gene array analysis has revealed that treatment with anti-CD154 mAb (MR1) had distinctive impact on host immunity in naive vs sensitized animals. Unlike in naive counterparts, host sensitization mitigated the impact of CD154 blockade on critical immune signaling pathways. Indeed, we identified 3234 genes in cardiac grafts that were down-regulated by MR1 in naive (at least 5-fold), but remained unaffected in sensitized hosts. Moreover, MR1 treatment failed to prevent accumulation of CD4 T cells in cardiac allografts of sensitized recipients. Then, to determine the role of CD4 help in CD154 blockade-resistant immune response, we used CD4-depleting and CD4-blocking Ab, in conjunction with MR1 treatment. Our data revealed that CD154 blockade-resistant CD8 activation in sensitized mice was dependent on CD4 T cells. In the absence of CD4 help, CD154 blockade prevented differentiation of alloreactive CD8 T cells into CTL effector/memory cells and abrogated acute rejection (cardiac graft survival for >30 days), paralleled by selective target gene depression at the graft site. These results provide the rationale to probe potential synergy of adjunctive therapy targeting CD4 and CD154 to overcome graft rejection in sensitized recipients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI23847 and AI42223 (to J.W.K.-W.), the American Heart Association (to Y.Z.), and the Dumont Research Foundation.

² Current address: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’anJiaotong University School of Medicine, Xi’an, Shangxi Province, China 710061.

³ Address correspondence and reprint requests to Dr. Jerzy W. Kupiec-Weglinski, Dumont-University of California Transplant Center, Room 77-120 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: jkupiec{at}mednet.ucla.edu

⁴ Abbreviations used in this paper: CTLe, effector CTL.