The research proposed in this project is designed to investigate the mechanisms of allogeneic stem cell development into mature and functioning T and B cells in humans with severe combined immunodeficiency (SCID). SCID infants who have become chimeric after receiving T cell-depleted allogeneic bone marrow stem cells without pretransplant cytoreduction or post-transplant GVHD prophylaxis provide a rare opportunity to study the mechanism of development of phenotypically normal T (and, in some cases, B and NK) cells from normal stem cells in an iatrogenically unaltered microenvironment.
The First Aim i s to study the mechanism of T cell development in human SCID infants given haploidentical T cell-depleted parental marrow stem cells and the characteristics of those T cells. Three hypotheses will be tested: a) that the maturation of normal stem cells to phenotypically and functionally normal T cells may not always occur in the SCID infant's thymus, b) that the T cells in some infants may derive from transplacentally acquired maternal T cells that persist and become expanded after stem cell transplantation, and c) that the T cells that develop extra-thymically or by expansion of transplacentally-transferred maternal T cells will have a restricted TCR Vbeta repertoire.
The Second Aim i s to study the mechanism of apparent tolerance to host antigens of T cells that develop from donor stem cells in human SCID chimeras. Two hypotheses will be tested: a) that donor T cells are 'tolerant' to host tissue antigens due to immune deviation resulting from a T cell cytokine imbalance and b) that such tolerant T cells can become cytotoxic T cells in the presence of an appropriate cytokine.
The Third Aim i s to determine whether the B cells that are present in human SCID infants function poorly following stem cell transplantation because of intrinsic abnormalities in the B cells or as a result of defective collaboration with the tolerant haploidentical genetically-donor T cells that develop.
The Fourth Aim i s to determine whether the B cell functional deficiency in SCID recipients of T cell-depleted bone marrow stem cells derives from restricted utilization of immunoglobulin (Ig) genes. Two hypotheses will be tested initially a) that Ig gene utilization differs among the different molecular forms of SCID and b) that the extent of Ig gene utilization also changes with time post-transplantation.
Showing the most recent 10 out of 13 publications
