Adolescent Health in Myanmar
Support Burnet’s Adolescent Health Programs in Myanmar today.
Support Burnet’s Adolescent Health Programs in Myanmar today.
Support Burnet’s Adolescent Health Programs in Myanmar today.
Support Burnet’s Adolescent Health Programs in Myanmar today.
The effects of a variety of metabolic and anti-tumour necrosis factor (TNF) antibodies were utilized to distinguish several different mechanisms of cytotoxicity employed by CD4+ effectors isolated from human peripheral blood lymphocytes (PBL). PBL, unseparated high buoyant density T cells and their CD4+ T cell subsets were activated with anti-CD3 monoclonal antibody (MoAb) and interleukin-2 (IL-2) for 1-5 days. CD4+ T cells activated with IL-2/anti-CD3 MoAb were cytotoxic when directed by a bispecific anti-nitrophenyl (NP)-anti-CD3 MoAb heteroconjugate against both NP-modified nucleated target cells (TC) and non-nucleated sheep red blood cells (SRBC). This CD4+ T population also lysed L929 in a TNF-alpha dependent manner. Interestingly, different mechanisms of nucleated and non-nucleated TC directed lysis by CD4+ effectors were implied by distinct patterns of sensitivity to cholera toxin (CT) and cyclosporin A (CsA). Cyclosporin A and CT inhibited CD4+ T cell directed lysis of SRBC, but not EL4. Cholera toxin, CsA or EGTA pretreatment also significantly inhibited the release of alpha-N-benzyloxycarbonyl-L-lysine-thiobenzylester (BLT)-esterase activity suggesting that degranulation of CD4+ effectors may be a critical step in their redirected lysis of SRBC. Overall, these findings suggested that activated human peripheral blood (PB) CD4+ effectors can lyse TC by at least three distinct mechanisms: (i) a CsA-sensitive directed lysis of SRBC which correlates with exocytosis and presumably occurs via membrane lesions; (ii) a CsA-insensitive directed lysis of NP-modified nucleated TC that does not appear to involve exocytosis and is metabolically distinct; and (iii) a direct TNF-dependent lysis of TNF-sensitive TC. The highly proliferative CD4+ T cell population could be propagated for at least 35 days while retaining cytotoxicity and secreting up to 80 U/mL of IL-2. These data raise the possibility that anti-CD3 MoAb plus IL-2 activated CD4+ T cells may prove effective in adoptive tumour immunotherapy.