HIV-1 infection, bone marrow transplantation, and intensive chemotherapy are states of profound immune depression marked by peripheral T- lymphocyte depletion and deficiencies in cell-mediated immunity. Full recovery of the immune system requires complete reconstitution of the T cell repertoire. The thymus gland is the primary site of T cell development. Consequently, the state of thymic function in an immunodeficient individual may be a pivotal factor in immune reconstitution. The normal pattern of age-dependent thymic involution is apparently reversed in some pathologic states. Thymic enlargement has been observed in some adults with Grave's disease, after correction of Cushing's syndrome, or after recovery from chemotherapy. This implies that thymic reserve persists into adulthood and can be summoned. Recent data from our laboratory demonstrate abundant thymic tissue in a surprisingly large fraction of HIV-1+ adults. The presence of abundant thymus is significantly associated with increased total CD4+ cells and increased naive CD4+ T cells. We propose that HIV-1 mediated destruction of peripheral T cells induces production of a serum factor which feeds back upon the thymus to upregulate thymopoiesis. Our finding of abundant thymus and increased naive CD4+ cells in some adults with HIV-1 infection provides us with an ideal opportunity to examine regulators of thymopoiesis in HIV-1 disease.
The specific aims of this proposal are: (1) To optimize an in vitro assay system to measure regulators or human thymopoiesis; (2) To analyze HIV-1+ human sera for the presence of known and unknown regulators of thymopoiesis, and (3) To determine whether putative positive and/or negative regulators of thymopoiesis are active in vivo using the SCID-hu Thy/Liv mouse model.
| Hanley, Mary B; Napolitano, Laura A; McCune, Joseph M (2005) Growth hormone-induced stimulation of multilineage human hematopoiesis. Stem Cells 23:1170-9 |
