Hong Xu, M.D.

h0xu0001@louisville.edu 
Assistant Professor (Term)
Beijing Medical University, 1988

Nonmyeloablative Conditioning Strategies for Bone Marrow Transplantation: Hematopoietic mixed chimerism is a state of coexisting hematolymphopoietic cells of donor and recipient origin. This state can be achieved in immunologically competent recipients through nonmyeloablative conditioning that do not eradicate host immune system. We have made significant progress in developing an immune-based non-myeloablative conditioning strategies to achieve mixed chimerism and donor-specific tolerance with minimum conditioning. 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 with monoclonal antibodies or drugs. We 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. We have demonstrated that host pretreatment with anti-αβ-TCR, anti-CD154, and rapamycin lowers the requirement of total body irradiation (TBI) for engraftment and the systemic donor-specific immune tolerance is achieved in mixed chimeras with non-myeloablative conditioning.  We have also defined a critical role for innate immunity in allogeneic hematopoietic cell rejection via the TLR4/TRIF pathway. We demonstrated that, by depleting host innate immune cells of NK cells and macrophages, TBI can be reduced to safe and clinically acceptable levels in a mouse BMT model. Currently, we are working on novel strategies for establishing mixed chimerism by inhibiting the various immune signalling pathways as an alternative to immune cell reduction.

The management of allosensitization in transplantation:  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. We have found that mixed chimerism can be induced through immune deviation of adaptive immunity in sensitized recipients and sensitization can be totally prevented at the time of exposure to alloantigen by blocking the CD154 costimulatory molecule. Currently, we are working on defining the mechanisms of bone marrow cell rejection in sensitized recipients. Which mechanism is dominant in bone marrow cell rejection: the complement-dependent cytotoxicity (CDC) vs. antibody-dependent cell-mediated cytotoxicity?

Mixed chimerism induces donor-specific tolerance to VCA:  The overall objective of this proposal is to advance vascularized composite tissue allotransplantation (VCA) and promote drug-free acceptance of organ and tissue transplants.  Thousands can benefit from transplantation of VCA to replace lost limbs and massive skin, muscle, nerve and bone defects. The technical feasibility of VCA is established, as reflected by numerous successful hand transplants, facial reconstructions, and successful replacement of larynx, vascularized knee, and other tissues. Our research addresses the problems that currently prevent the widespread application of CTA: the need for long-term non-specific immunosuppression with their associated toxicities and concerns regarding chronic rejection. Overcoming these obstacles, through the induction of donor-specific tolerance, is the holy grail of transplantation.  Our focus of this research program is to develop a clinically applicable approach to enable the widespread application of mixed chimerism to induce donor-specific tolerance to VCA.  We have successfully transitioned to the sequential VCA model to a simultaneous VCA model, which has greater clinical implications.  In presensitized recipient, we have found that VCA were rejected in an accelerated fashion but not hyperacutely. The rejection of VCTA in sensitized recipients is mainly cell mediated and differs mechanistically from that for renal transplants. We continue to work on new treatments that will be safer and will be able to be transferred to clinic to induce donor-specific tolerance.

10 Publications:

1. Xu, H, Zheng, X.X., Zhang, W., Huang, Y., and Ildstad, S.T.: A critical role for TGF-β/Fc and nonlytic-IL-2/Fc fusion proteins in promoting chimerism and donor-specific tolerance.  Transplantation, 2016 Jun 14. [Epub ahead of print]. 
2. Xu H, Huang Y, Hussain LR, Zhu Z, Bozulic LD, Ding C, Yan J, Ildstad ST. Sensitization to minor antigens is a significant barrier in bone marrow transplantation and is prevented by CD154:CD40 blockade. Am J Transplant. 2010 Jul;10(7):1569-79. PMID: 20642683
3. 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. 2008 Mar 15;111(6):3266-75.

2. Xu H, YanJ, Zhu Z, Hussain LR, Huang Y, DingC, Bozulic LD, Wen Y, and Ildstad ST. A Critical Role for the TLR4/TRIF Pathway in Allogeneic Hematopoietic Cell Rejection by Innate Immune Cells. Cell Transplant. 2013;22(12):2367-80.
3. XuH, RamseyDM, Wu S, Bozulic LD, and Ildstad ST. Simultaneous bone marrow and composite tissue transplantation in rats treated with nonmyeloablative conditioning promotes tolerance. Transplantation, 2013 Jan 27;95(2):301-8.
4. Xu H, Zhu Z, Huang Y, Bozulic LD, Hussain LR, Yan J, Ildstad ST. Innate and Adaptive Immune Responses Are Tolerized in Chimeras Prepared With Nonmyeloablative Conditioning. Transplantation. 2012 Mar 15;93(5):469-76.

7. 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.
8. 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)
9. 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.
10. 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.