Investigations into the mechanisms of pathogenesis of chronic graft-vs.-host disease using a MHC-matched, minor antigen-mismatched murine model [electronic resource]

9780496724406

2004

1 online resource (169 p.)

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Allogeneic stem cell transplantation (alloSCT) is a potentially curative therapy for hematologic malignancies, inherited hematopoietic stem cell disorders, and possibly non-hematopoietic malignancies. Graft vs. host disease (GVHD) results from the recognition of host antigens by donor T cells, and is the major cause of morbidity and mortality limiting the wider applicability of alloSCT. GVHD has two manifestations, acute and chronic. Chronic graft vs. host disease (cGVHD) is increasingly common in recipients of alloSCT, but the fundamental immunologic mechanisms of initiation and maintenance of this disease are not understood. While acute GVHD (aGVHD) has been widely studied, there remains a paucity of research on cGVHD. Moreover, most studies have used models which do not accurately mirror current clinical transplantation. We revisited the B10.D2 → BALB/c CD4+ T cell-dependent murine model of cGVHD which uses lethally irradiated recipients, crosses minor histocompatibility antigens only, and shares many important features with human cGVHD. We used this model to determine that: (a) cGVHD is not a T2-disease, as previously hypothesized, and the hallmark of disease, fibrosis, is independent of IL-4; (b) donor CD4+ naive cells initiate cGVHD, but effector memory cells, while immunologically competent, do not cause cGVHD; (c) both donor and recipient CD4+CD25 + cells regulate the severity of cGVHD and; (d) both donor and recipient APCs stimulate donor T cells to cause cGVHD; recipient APCs are more important for initiation of skin cGVHD while donor APCs play a larger role in gastrointestinal (GI) cGVHD. These findings have enhanced our understanding of the immunobiology behind cGVHD and suggested novel therapeutic strategies to prevent or eliminate cGVHD: transplantation of memory cells may eliminate cGVHD while preserving immunity against common pathogens; specific preservation of recipient and donor CD4+CD25+ cells could minimize cGVHD and; timely elimination of recipient and donor APCs could reduce activation and clonal expansion of alloreactive donor cells.

Books / Online / Dissertations & Theses

English

July 12, 2011

Thesis (Ph.D.)--Yale University, 2004.

Yale University.