Resistance against engraftment by MHC matched allogeneic hematopoietic cell transplant following reduced intensity conditioning: Requirement for donor CD80/86 co-stimulation to elicit T cell mediated barrier responses dependent on perforin and fas ligand
Date of Award
Doctor of Philosophy (Ph.D.)
Microbiology and Immunology
First Committee Member
Robert B. Levy, Committee Chair
Reduced intensity conditioning has shown promise in reducing complications such as graft versus host disease, organ toxicity, and post-transplant infections, however immune mediated graft failure represents a significant limitation to widespread application. In the current study, a model of resistance following reduced intensity MHC matched allogeneic HCT was developed. The contribution of CD4+ and CD8+ T cell subsets in this barrier response was investigated post-transplant in CD4-/- or CD8-/- recipients. Resistance was weaker in the absence of either CD4+ or CD8+ T cells demonstrating involvement of both subsets in this resistance to minor histocompatability antigens (MiHAs). Interestingly, the CD4+ T cell subset was capable of exhibiting a dual role by providing both help in generating an optimal CD8+ T cell response as well as effecting resistance in the absence of host CD8+ T cells. The importance of the major cytotoxic pathways perforin and fasl in resistance was also investigated. Effector cells derived from naive T cells were critically dependent on perforin and fasl to effect resistance, whereas effector populations derived from memory T cells were able to mediate efficient resistance in the absence of these pathways. Finally, the involvement of CD80 and CD86 co-stimulatory molecules in the development of this T cell resistance was examined. Global blockade of CD80 and CD86 by infusion of anti-CD80 and CD86 mAbs resulted in sustained engraftment. The importance of CD80/CD86 expression limited to host or donor cells was compared with respect to the development of resistance. The absence of CD80 and CD86 expression in the host did not diminish resistance, whereas, the absence of CD80 and CD86 on the donor graft led to sustained engraftment and the development of tolerance to donor and host MiHAs. The results indicate that inhibition of signaling mediated by CD80 and/or CD86 on donor BM may effectively improve donor engraftment while maintaining an optimal GVL or anti-pathogen immune response. Findings in this investigation also support the notion that transplant parameters such as the donor/recipient genetic disparity and the presence of anti-donor alloreactive memory T cells must be considered in the development of effective strategies to overcome resistance following HCT.
Health Sciences, Immunology
Zimmerman, Zachary Franklin, "Resistance against engraftment by MHC matched allogeneic hematopoietic cell transplant following reduced intensity conditioning: Requirement for donor CD80/86 co-stimulation to elicit T cell mediated barrier responses dependent on perforin and fas ligand" (2005). Dissertations from ProQuest. 2221.