Development of lymphopoiesis as a function of the thymic microenvironment. Use of CD8+ cytotoxic T lymphocytes for cellular immunotherapy of human cancer.

The mammalian thymic histogenesis can be immunomorphological divided into three consecutive states: 1) Epithelial: 2) Lymphopoietic or lympho-epithelial and 3) Differentiated cellular microenvironment with formation of Hassall's bodies. The embryonic, epithelial pharynx serves as the origin of the mammalian thymus. The epithelial cell layer of endodermic origin expands into pharyngeal pouches and the thymic anlagen are formed from the dorsolateral portions of the third pharyngeal pouch. In absence of humoral and cell to cell interactions with the ectomesenchyme, the primary epithelial anlagen are unable to proliferate. Experimental or spontaneous neural crest ablation early in ontogenesis also results in non-physiologic thymic organogenesis. Earlier thymic studies detected a subcapsular A2B5+ and Thy-11+, TE4+, Vimentin+, Cytokeratin+ endocrine reticulo-epithelial cell or nurse cell subpopulation within the cortical reticulo-epithelial cell network. Secretion of multiple in situ active, autocrine growth factors and a humoral chemotactic factor by the cells of ectomesenchymal origin allows the commencement of immigration of hemopoietic stem cells. The thymic lymphopoiesis is initiated by the immigration of pluripotent (with cellular immunophenotype TdT+, Ki67+, CD3-, CD7+, CD34+, CD38+, CD44+, CD45+ or T200+), but already to T lymphocyte cell lineage committed hemopoietic stem cells during the 6-7th week of ontogenesis. CD2, a 50-55 kD glycoprotein is the first intrathymic, early differentiation antigen expressed during the 8-9th ontogenetic weeks. This antigen also serves as a cell surface component of the alternative or antigen independent pathway of thymocyte activation. The 10th week is defined as the first expression of CD4 and CD8 antigens which determine the basic, characteristic dichotomy of the T lymphocytes. The induction of the initial proliferative wave of immature cortical thymocytes is carried out by the LFA-3 (CD58) adherence molecules, the receptors of CD2 antigens located on reticulo-epithelial cells. As a result of the extremely high proliferation rate the thymic mass markedly expands in all dimensions and numerous microlobules are formed. Between the 13th to 16th week the typical thymic cell environment is formed and the first Hassall's bodies are developed. The outer layer of the bodies contain hypertrophized TE8+, TE16+ and TE19+ reticulo-epithelial cells, with an active secreting cytoplasmic structure. Cytotoxic cells express special receptors by which they are capable to distinguish altered or foreign cells from autologous cells of the host. Solid human tumors are characterized with a marked poly- and mononuclear cell infiltrate containing phagocytes, various subtypes and clones of lymphocytes and granulocytes.(ABSTRACT TRUNCATED AT 400 WORDS)