Anita S. Chong, Ph.D.

Transplantation Tolerance, Mechanisms of Rejection, and the Regulation of T and B Cell Responses to Allografts

Research Summary

The central theme of my research is to understand how the immune system discriminates between self-and non-self and how immune events subsequent to this discrimination event are regulated. The primary focus of my research on basic and translational issues of transplant tolerance. The possibility that tolerance to a transplanted organ can be induced is tremendously attractive, as it would obviate the need for expensive and dangerous chronic immunosuppression. However, it has become clear that, despite the numerous successes in inducing tolerance in rodent transplant models, transplant tolerance in humans remains an elusive goal. My laboratory has developed a tolerance-induction strategy in mice, involving the transplantation of intact bone fragments as a stable source of donor cells along with transient therapy with anti-CD40 monoclonal antibodies. We are actively investigating the mechanism for allograft tolerance, focusing on peripheral regulatory events.

A second area of investigation for my laboratory stems from the realization that the supply of human organs cannot adequately satisfy the needs of humans requiring transplantation. Thus, for transplantation to realize its potential in the treatment of human disease, alternative sources of organs must be developed. I thus decided to devote some of my research efforts to understanding the immunology of antibody-mediated xenograft rejection and accommodation.
We believe that these studies, which will elucidate what properties of antibodies determine whether they are pathogenic, non-pathogenic or even protective, will have application to xenotransplantation and also provide insights into the roles of antibodies in allotransplantation.

The third area of investigation in my laboratory focuses on issues related to the application of islet transplantation as a cure for Type I diabetes. We have developed a project that aims at defining and preventing the early inflammatory events that result early islet destruction following intraportal injection. More recently, we have embarked on studies investigation alternative sources of islet stem cells.

Selected Papers

Ogawa H, Mohiuddin MM, Yin DP, Shen J, Chong AS, and Galili U. 2004. Mouse-heart grafts expressing an incompatible carbohydrate antigen. II. Transition from accommodation to tolerance. Transpl. 77:366.

Yin, D-P, Zeng, H, Ma, L, Shen, J, Byrne, GW, and Chong, AS. 2004.  Cutting Edge: Natural killer (NK) cells mediate IgG1-dependent hyperacute rejection of xenografts. J Immunol: 172:7235.

Hara, M, Yin, D, Dizon, RF, Han, M, Shen, J, Chong, AS, and Bindokas, VP. 2004.  A mouse model for studying intrahepatic islet transplantation. Transplantation 78:615.

Li, D, Gal, I, Vermes, C, Alegre, M-L, Chong, ASF, Chen, L., Shao, Q, Vyasheslava, A, Xu, X, Koreny, T, Mikecz, K, Finnegan, A, Glant, TT, and Zhang, J. 2004.  Cutting Edge:  Cbl-b:  A key molecule involved in CD28- and CTLA-4 mediated T cell costimulation.  J. Immunol.  173:7135.

Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber, H and Fu, YX.  2005.  Intra-tumor depletion of CD4+ cells unmasks tumor immunogenicity leading to rejection of established tumor. J Exp Med 201:779.

Yin, D, Ding, D, Shen, J, Ma, L, Hara, M, and Chong, AS.  2006.  Liver ischemia contributes to early islet failure following intraportal transplantation: Benefits of liver ischemic-preconditioning. Am J. Transpl. 6: 60.

Chong, AS, Zeng, H, Knight DA, Shen J., Meister GT, Williams, JW, and Waldman J.  2006. Concurrent Anti-viral and Immunosuppressive Activities of Leflunomide in vivo.  Am J. Transpl. 6:  69.

Chong, AS, Shen, J, Tao, J, Yin, D, Kunetzov, A, Hara, M, and Philipson, LH.  2006. Reversing diabetes in NOD mice without spleen cell-derived beta-cell regeneration. Science 311:1774-5.

^Chen, L, ^Wang, T, Zhou, P, Ma, L, Yin, D, Shen, J, Molinero, L, Nozaki, T, Phillips, T, Wang, C-R, Fairchild, RL, *Alegre, M-L, and *Chong, AS. 2006. TLR Engagement Prevents Transplantation Tolerance.  Am. J. Transpl. 6: 2282. ^Co-first author; *Co-last author.

Yin, D, Tao, J, Lee, DD, Shen, J, Hara, M, Lopez, J, Kunetzov, A, and Philipson, LH, and Chong, AS.  2006.  Recovery of islet beta-cell function in streptozotocin-induced diabetic mice:  An indirect role for the spleen. Diabetes 55:3256-63.

Chong, AS, Shen, J, Tao, J, Yin, D, Kunetzov, A, Hara, M, and Philipson, LH.  2006. Response to Comment on Chong et al. on Diabetes reversal in NOD mice.  Science 314:1243.

Kirk, AD, Baldwin, WM, Cascalho, MI, Chong, AS, Sykes, M, West, LJ.  2007. American Society of Transplantation symposium on B cells in transplantation: harnessing humoral immunity from rodent models to clinical practice. Am. J. Transplant. 7:1464.

Li, Y, Ma, L, Yin, D, Shen, J and Chong, AS.  2007. Peripheral Deletion of Allo-reactive B Cells Induced by Costimulation Blockade.  Proc. Nat. Acad. Sc. 104:12093.

Ding, JW, Zhou, TT, Zeng, HZ, Ma, L, Verbeek2, JS, Yin, D, Shen, J, and Chong, AS.  2008. Hyperacute rejection by anti-Gal IgG1, IgG2a and IgG2b is dependent on complement and Fc-gamma receptors.  J. Immunol. 180:261-68

Ding, JW, Zhou, TT, Ma, L, Yin, D, Shen, J, Ding, CYP, Tang, IY, Byrne, GW and Chong, AS.  2008.  Expression of complement regulatory proteins in accommodated xenografts induced by anti-α-Gal IgG1 in a rat-to-mouse model. Am. J. Transplant.  8:32-40

Ma L, Xiang Z, Sherrill TP, Wang L, Blackwell TS, Williams P, Chong A, Chari R, Yin DP.  2008. Bioluminescence imaging visualizes activation of nuclear factor-kappaB in mouse cardiac transplantation.  Transplantation 85:903-910.

Alegre ML, Leemans J, Le Moine A, Florquin S, De Wilde V, Chong A, Goldman M. 2008. The Multiple Facets of Toll-Like Receptors in Transplantation Biology.  Transplantation 86:1-9.

Xiang Z, Ma LL, Manicassamy S, Ganesh BB, Williams P, Chari R, Chong A, Yin DP. 2008.  CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice.  Transplantation 85:1205-11.

Li Y, Ma L, Yin D, Shen J, Chong AS. 2008.  Long-term control of alloreactive B cell responses by the suppression of T cell help.  J Immunol.180:6077-84.

Wang T, Chen L, Ahmed E, Ma L, Yin D, Zhou P, Shen J, Xu H, Wang CR, Alegre ML, Chong AS. 2008.  Prevention of allograft tolerance by bacterial infection with Listeria monocytogenes.  J Immunol.180:5991-9.

Lee DD, Grossman E, Chong AS. 2008.  Cellular therapies for type 1 diabetes.  Horm Metab Res. 40:147-54. Review.