Physiology & Biophysics

HONG XU, M.D.
h0xu0001@louisville.edu 
Assistant Professor
Beijing Medical University, 1988

The management of allosensitization in transplantation:  sensitization reversal and prevention
Sensitization of patients to MHC antigens is among the most critical challenges in clinical transplantation. Patients with preformed antibodies have higher rejection rates and inferior outcomes for bone marrow transplantation and organ transplantation. Induction of mixed allogeneic chimerism has been demonstrated to confer donor-specific tolerance in the setting of allosensitization. Our recent work in developing a nonmyeloablative approach to establish chimerism in sensitized recipients found that humoral immunity poses a dominant barrier, with T-cell reactivity secondary, but still significant. The CD154:CD40 interaction is required for effective activation of both T- and B-cells. Currently, we are working to induce immune deviation of adaptive immunity in sensitized recipients to establish mixed chimerism. We are also trying to examine whether sensitization could be prevented at the time of exposure to alloantigen.

Nonmyeloablative Conditioning Strategies for Bone Marrow Transplantation

As new mechanisms as well as new agents have been defined in transplantation tolerance, it has made it possible to develop new strategies to further reduce the requirement of conditioning to allow the engraftment to occur by targeting these defined specific effector cells or pathways with monoclonal antibodies or drugs. W are working to develop more clinical acceptable nonmyeloablative (and therefore, less toxic) conditioning strategies for the establishment of mixed chimerism to induce donor-specific tolerance.

Publications:

1. Xu H, Yan J, Huang Y, Ding C, Schanie CL, Wang L, Chilton PM, and Ildstad ST.  Induction of B and T cell tolerance by co-stimulatory blockade (anti-CD154) in combination with T cell lymphodepletion results in profound prevention of sensitization.  Blood 2007: DOI 10.1182/blood-2006-10-053801
2. Xu H, Chilton PM, Huang Y, Schanie CL, Yan J, and Ildstad ST. Addition of cyclophosphamide to T-cell depletion-based nonmyeloablative conditioning allows donor T-cell engraftment and clonal deletion of alloreactive host T-cells after bone marrow transplantation. Transplantation. 2007 Apr 15;83(7):954-63.
3. Xu H, Chilton PM, Tanner MK, Huang Y, Schanie CL, Dy-Liacco M, Yan J, and Ildstad ST. Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients. Blood. 2006;108:3611-3619)
4. Xu H, Chilton PM, Huang Y, Schanie CL and Ildstad ST.  Production of donor T cells is critical for induction of donor-specific tolerance and maintenance of chimerism. Journal of Immunology, 2004 Feb 1;172(3):1463-71.
5. Xu H, Exner BG, Chilton PM, Tanner MK, Mueller YM, Rezzoug F and Ildstad ST. A delay in bone marrow transplantation after partial conditioning improves engraftment. Transplantation. 2004 Mar 27;77(6):819-26.
6. Xu H, Beate G. Exner, Chilton PM, Schanie CL and Ildstad ST.  CD45 Congenic Bone Marrow Transplantation:  Evidence for T cell Mediated Immunity. Stem Cells, 2004;22(6):1039-48.
7. Xu H, Exner BG, Cramer D, Tanner M, Mueller YM, Ildstad ST.  Characterization of cell populations in the recipient hematopoietic environment that mediate resistance to engraftment of allogeneic donor bone marrow.  Journal of Immunology, Volume 168 / No. 3 / February 1, 2002.