To study the pathogenesis and preventive strategies of acute and chronic graft-versus-host disease (aGVHD, cGVHD) after hematopoietic stem cell transplantation (HSCT), murine models of aGVHD and cGVHD were constructed. In addition, the role of CD4+CD25+ regulatory T cells (Tregs) in GVHD was also investigated in these models.
My project consisted of three parts, including MHCI,II mismatched (part 1) and haploidentical BMT(part2) based aGVHD, and MHC matched, minor histocompatibility antigen (miHA)mismatched cGVHD(part 3).
In the first model, aGVHD resulting from an MHC I, II mismatched aGVHD (B6(H-2b)→BALB/c(H-2d)) HSCT was studied, particularly with respect to the role that CD4+CD25+Tregs played. The results showed that CD4+CD25-T-cells induced more severe aGVHD than CD4+ T-cells, resulting in more extensive
target organ lesions, especially in colon. The possible mechanism might be due to the enhanced proliferation and differentiation towards pathogenic Th1 cells.
In the second model, haploidentical (B6(H-2b)→[C57BL/6×CBA/Ca]F1(H-2b×k)) HSCT was used to studied the role of CD4+or CD8+T-cells in aGVHD.Both high dose of donor CD4+-and CD8+-T-cells have the ability to induce lethal aGVHD in the hosts. However, the clinical and histological features of aGVHD induced by CD4+T-cells were significantly different from that induced by CD8+T-cells. Both donor CD4+-and CD8+-T-cells showed marked proliferation and differentiation towards CD4+IFN-γ+Th1and CD8+IFN-γ+cells, respectively. Polyclonalexpanded freshly isolatednTregs (exp-nTregs) showed obvious proliferation, increased apoptosis, and rapid loss of Foxp3 expression with impaired suppressive function. Exp-nTregs were further investigatedfor their preventive function in aGVHD in this haploidentical HSCT model. The results showed that exp-nTregs were capable of attenuating either CD4+-or CD8+-T-cell-induced aGVHD with significantly prolonged survival rate.
In the third model, cGVHD was investigatedin DBA/2 (H-2d)→BALB/c (H-2d) HSCT, where the biologic readout was proteinuria and skin fibrosis. The results showed that donor CD4+T-and B220+B-cells were the main effectors in the pathogenesis of cGVHD. Notably, a more active germinal center (GC) reaction existed in the cGVHD cohorts compared with the control syngeneic cohort. Furthermore, Tfh and GC B-cells were shown to have originated from donor CD4+T-and B220+B-cells, respectively. Importantly, Tfh and GC B cells were mutually stimulatory and inter-dependent.
In conclusion, three murine models were used to investigate aGVHD and cGVHD. The results showed that Tregs played a significant suppressive role in aGVHD complicating haploidentical HSCT. Furthermore, a hyperactive germinal center reaction might be the main cause of cGVHD. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/188282 |
| Date | January 2012 |
| Creators | Shao, Liang, 邵亮 |
| Contributors | Kwong, YL |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B50534014 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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