INHIBITION OF LYMPHOCYTE-PROLIFERATION BY AMANTADINE AND ITS ISOMER, 2-AMINOADAMANTANE - IMPACT ON LYT-2+ T-CELLS WHILE SPARING L3T4+ T-CELLS

The present in vitro investigations on amantadine (AmTd) and its isomer 2-aminoadamantane (2-NH2-Adam), and the corresponding analogs, 1-nitroadamantane (1-NO2-Adam) and 2-nitroadamantane (2-NO2-Adam), were undertaken to gain information about molecular features that might have a dominant role in inhibiting T lymphocyte proliferation and to determine whether all, or a subpopulation of thymic-dependent (T) lymphocytes might be impacted by these drugs. Studies were done using lymphocytes from untreated normal mice as well as cloned murine cytotoxic T lymphocytes, CTLL cells. T lymphocytes were defined by their proliferative response to concanavalin A (Con A), and thymic-independent (B) lymphocytes by their proliferative response lipopolysaccharide (LPS). Proliferation of CTLL cells was induced by supplementing the culture medium with lymphokine-containing medium or by adding reconbinant interleukin (IL)-2. Proliferation was assessed by quantifying cellular incorporation of tritiated thymidine. The data show that the aminoadamantanes, AmTd and 2-NH2-Adam, impacted on Lyt-2+ T lymphocytes while sparing L3T4+ T lymphocytes. In addition, the data show that the location of the substituent group on the adamantane ring altered the molecule's capacity to modulate lymphocyte activity. And finally, results of studies comparing the inhibitory activity of AmTd and 1-NO2-Adam suggest a non-lysosomal mechanism of action. Possible implications of these findings are discussed.