In order for T cell activation and subsequent functional programs to occur, T cells must not only see foreign antigen peptide in the context of MHC but they must also receive a """"""""second signal"""""""" which can be provided by a number of accessory molecules such as CD28/CTLA-4, CD5, CD2, LFA-1, which are expressed on the surface on the T cell. We have recently established the identity of additional costimlatory molecules, CD26, VLA/CD29 and CD27 in which both VLA/CD29 and CD26 play an important role in the costimulation of CD45RO+CD29+ memory T cells, whereas CD27 plays an important role in the costimulation of CD45RA+ CD45RO- naive T cells. In this regard, we found that the T cells obtained from post allo-BMT patients exhibited prolonged impairment of T cell proliferative response triggered by immobilized anti-CD3 plus anti-CD29/VLAbeta mAb or immobilized extracellular matrix proteins (ECMs) compared with T cells from normal controls. The major goal of this proposal (project 2) is to determine the cellular and molecular defects in immunoregulatory T cells in patients after allo-BMT.
The specific aims of this proposal are: 1) The molecular nature of the defect of VLA-mediated T cell costimulation will be determined. The reconstitution of ppl 25FAK, ppl 05, other tyrosine phosphorylated proteins induced by ligation of VLA-4 and that of FAK- associated molecules involved in VLA mediated T cell costimulation will be studied. Moreover, the defect of the downstream events of VLA-mediated T cell costimulation will be determined. 2) The costimulatory activity of memory T cells via the CD26 will be determined. The immune reconstitution of CD26 mediated costimulation and the molecular basis for the defect of CD26 mediated costimulation will be studied. Moreover, the immunoenhancing effect of recombinant soluble CD26 on antigen-specific T cell response (TT and CMV) in allo-BMT patients and the levels of sCD26/DPPIV in serum/plasma and its correlation with clinical complications of allo-BMT will be determined. 3) The costimulatory activity of naive T cells via the CD27 will be determined. The immune reconstitution of CD27 mediated costimulation and CD27-ligand in the course of allo-BMT will be studied. Moreover, the CD27 mediated biochemical signaling events in such patients will be determined. In addition, the levels of sCD27 in serum/plasma and correlation with clinical complication of allo-BMT will be determined. 4) The molecular basis for T cell abnormalities in patients with GVHD following allo-BMT based on the above molecules (CD29/VLA, CD26 and CD27) will be determined. Our projects would provide important insights into understanding the precise molecular mechanisms of immune dysfunction following allo-BMT as well as the pathophysiology of GVHD seen after allo- BMT. More importantly, these projects will yield new concepts for developing rational therapy for the manipulation of the defects found in such patients.
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