Title

Facilitation of allogeneic hematopoietic engraftment by donor CD4+CD25+ T cells

Date of Award

2004

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Robert B. Levy, Committee Chair

Abstract

Allogeneic bone marrow transplantation is a potentially curative treatment for both inherited and acquired diseases of the hematopoietic compartment, but the wider use of allogeneic BMT is limited by the frequent and severe outcome of graft vs. host disease. Although unfractionated CD4 T cells have not been shown to be an efficient facilitating population, CD4+CD25 + regulatory (T-reg) cells were specifically investigated for the capacity to support allogeneic hematopoietic engraftment. In a murine fully MHC-mismatched BMT model, co-transplantation of donor B6 T-regs into sublethally conditioned BALB/c recipients supported significantly greater lineage committed and multi-potential donor progenitors in recipient spleens one week after transplant and significantly increased long-term multi-lineage donor chimerism. Donor engraftment occurred without GVHD-related weight loss or lethality and was associated with tolerance to donor and host antigens as demonstrated by in vitro and in vivo analyses. In order to define the initial events required for long-term engraftment and tolerance to develop, the host's resisting cell populations targeted by donor T-regs and the antigenic requirements for activating this T-reg mediated facilitation of early engraftment were investigated. Co-transplanting B6 T-regs augmented donor colonies when the recipients' T-cell resistance was removed by transplanting B6 BM-TCD into BALB/c Rag1-/- or into BALB/c x B6 F1 recipients. These results demonstrated that donor T-regs did not require suppression of recipient T cells in order to support donor progenitors. In contrast to the absence of T cell resistance, removal of NK resistance by transplanting BALB/c x B6 F1 BM-TCD into BALB/c recipients did increase the baseline level of progenitors detected. Despite the elevated baseline, co-transplanted B6 T-regs were able to increase the progenitor colony numbers detected in the absence of NK resistance. In summary, donor CD4+CD25 + T cells were found to be capable of supporting long-term allogeneic hematopoietic engraftment without inducing GVHD. Donor progenitor activity was supported as early as within the first week post-transplant, in the presence of a primarily NK mediated resistance. This early facilitation can occur without suppression of host resistance, and the independence from T cell suppression suggests a novel biological function of this regulatory population. Furthermore, the requisite co-transplantation with "self" marrow expressing MHC class II suggests that early facilitation is initiated following donor T-reg activation by direct recognition of transplanted donor APC. Donor CD4+CD25+ T cells thus represent a potential alternative to unfractionated T cells for promotion of allogeneic engraftment in clinical hematopoietic transplantation for both inherited and acquired diseases. (Abstract shortened by UMI.)

Keywords

Health Sciences, Immunology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3159132