The design of effective immune therapies to eradicate residual malignant cells following chemotherapy is dependent on understanding immune and hematopoietic dysfunctions present in this period. Toward this end, we have examined four facets of cellular function in patients with cancer before and after therapy. First, we have determined through preclinical animal models and clinical studies that the majority of CD4+ T cells present in the post-chemotherapy period are derived in adult patients from expansion of mature peripheral T cells. Population of T cells derived from expansion later decline in number and are susceptible to apoptosis. The resulting T cell repertoire is oligoclonal with clonal deficits as well as over-representations. Two clinical studies have been initiated based on these results with the intent to derive strategies to maximize T cell immunocompetence in adult patients treated with chemotherapy and to investigate NK cell biology and regeneration. The second facet of cellular function concerns the in vitro generation of T lymphocyte populations of defined cytokine phenotype: Type I (Th1, Tc1) and Type II (Th2, Tc2). CD4+ T cells of Th1-type mediated both lethal GVHD and GVL. In contrast, CD8+ cytotoxic T cells secreting either Type I or Type II cytokines were found to mediate potent GVL effects with reduced GVHD. Culture conditions have now been established for the generation of human cytokine-defined T cell subsets as a prelude to clinical studies. The third facet of the work concerns characterizing alterations in hematopoietic cell populations following chemotherapy. It was found that chemotherapy damage to hematopoietic progenitors occurred despite hematopoietic cytokine therapy. Such treatment stimulated production of negative regulators of hematopoiesis. The chemokine Mig has been identified as one such negative regulator. These results have implications for T cell regeneration and for gene manipulation of hematopoietic stem cells. The fourth facet of the work has focused on antigen presenting cell biology. It has been found that cells of monocyte /macrophage lineage are precursors of dendritic cells, and that calcium ionophore treatment of such cells provokes almost uniform conversion to cells of dendritic phenotype. Application of these findings to clinical studies is in progress. - Human Subjects & Human Tissues, Fluids, Cells, etc.
