Background: The recovery of CD4 T cells after high-dose chemo/radiotherapy in adult patients with cancer or autoimmune diseases is very slow (years) and may result in only limited T cell repertoire. A similar problem exists in AIDS patients treated with highly active anti-retroviral therapy. With the ultimate goal of designing strategies to improve the T cell regeneration after T lymphocytopenia, here we propose to study the mechanism of the T cell regeneration. Hypothesis: We hypothesize that after T-lymphocytopenia a substantial number of regenerating T cells originate from hemopoietic progenitors in young individuals whereas only few, if any, T cells originate from hemopoietic progenitors in older individuals. Instead, in the older individuals, the vast majority of T cells originate from the expansion of preexisting T cells. Methods: This hypothesis will be tested in severely lymphocytopenic patients with autoimmune diseases who have received high-dose chemo/radiotherapy plus anti-thymocyte globulin followed by autologous transplantation of hemopoietic (CD34+) cells. An extremely limited number of T cell clones survive such transplant conditioning/ CD34+ cell purification. Therefore, it is relatively easy (easier and more informative than in patients with only moderate T lymphocytopenia) to track down the fate of the surviving T cell clones and to detect T cells newly generated from hemopoietic progenitors post-transplant, using the following techniques: spectratyping, sequencing of the T cell receptor genes within a single spectratyping band, and quantifying T cells that contain T cell receptor-rearrangement excision circles (TREC). Outcome: If the above hypothesis is true, the repertoire of T cells, that is severely limited within the first several months after transplant, will later diversify in young (less than 5-years-old) whereas it will stay severely limited in older (greater than 45-years-old) patients. Also, if the hypothesis is true, the number of TREC-containing T cells post-transplant will be significantly higher in the young compared to the older patients. This will give impetus for developing strategies to enable older patients to generate T cells from hemopoietic progenitors, e.g., using thymopoietic cytokines or thymus grafting.
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