Bone marrow transplantation (BMT) now constitutes a major therapeutic option in the treatment of cancer patients. Despite increases in the use and success of BMT in many institutions, morbidity and mortality from infection post-transplant remain major problems. The re-establishment of normal T-cell responsiveness is an essential component in the development of resistance to infectious disease following BMT. This is particularly important for dealing with the latent viruses, Cytomegalovirus (CMV) and Epstein Barr Virus (EBV). In the absence of adequate T-cell responsiveness, these viruses are often fatal. Past experiments with a mouse model system for BMT have demonstrated that the patterns of T-cell receptor (TCR) gene rearrangements among developing T-cells in recipient animals are abnormal. Should a similar situation exist among human BMT recipients, the unusual susceptibility of recipients to infection, even in late stages following transplantation, may be explained. The present proposal will examine the regeneration of the TCR repertoire in pediatric cancer patients following BMT. Patients in this study will be recipients of autologous, HLA-matched, or HLA-mismatched marrow, and will differ accordingly in their susceptibility to infectious disease. RNA will be isolated from patient and control peripheral blood leukocytes (PBL) for the preparation of cDNA and analysis by the polymerase chain reaction (PCR), DNA cloning, and DNA sequencing methods. In addition, the TCR repertoire among EBV-specific T-cell clones established from patient and control PBL will be determined. These measures of T-cell quality will be correlated with the establishment of general T-cell function (to be assessed by proliferative responses to superantigens), the patient's ability to combat disease, and the ultimate success of the BMT procedure. The main hypothesis to be tested in this proposal is that the TCR repertoire available to the BMT recipient is abnormally restricted, yielding a qualitative as well as quantitative T-cell immunodeficiency. Information to be gained by the testing of the above hypothesis will be of substantial value, not only as a prognostic measure of BMT success, but as a guide for the development of future treatments aimed at the eradication of fatal infectious disease in BMT patients.
NIH ExPorter
NIH ExPorter