Low molecular weight human T-cell response immunopotentiator: alpha-2'-deoxy-3-deazaguanosine.
We have examined the immunological activity of a unique alpha-nucleoside analog of 2'-deoxyguanosine in which the pyrimidine ring nitrogen in the 3 position is replaced by CH [6-amino-1, 5-dihydro-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)imidazo[4,4-c] pyridin-4-one, alpha-d3DGuo, 1] and its structural analogs. The alpha-d3DGuo is not mitogenic to human PBL. It displayed consistently, however, a potent immunoenhancing activity on PHA-induced human lymphocyte proliferation at concentrations ranging from 0.0125 mM to 0.4 mM in a dose dependent manner. These findings thus suggest that mitogenicity is not a pre-requisite for the immunoenhancing effect. The maximal potentiating effect of alpha-d3DGuo is usually exerted at the bottom range of the dose response to PHA. The magnitude of increase is about the same as that mediated by rIL-2. Similarly, Con A mediated lymphocyte proliferation is markedly enhanced by alpha-d3DGuo. When added during allogeneic MLR, alpha-d3DGuo also augmented the proliferation of alloreactive T-cells and the magnitude of response was similar to that induced by rIL-2. The alpha-d3DGuo induced increase in allogeneic response was dependent on concentrations of both alpha-3dDGuo and alloantigens as noted with T-mitogen induced proliferative responses. The cytotoxic activity of lymphocytes induced in allogeneic mixed cultures was also augmented by alpha-d3DGuo. It showed, however, no potentiating effect on B-lymphocytes proliferation stimulated either with SAC or PWM. The alpha-d3DGuo is also able to restore, at least partially, the depressed proliferative responses of T-cells to both PHA and Con A.(ABSTRACT TRUNCATED AT 250 WORDS)
Sharma
B S
BS
ICN Nucleic Acid Research Institute, Costa Mesa, CA 92626.
Sanghvi
Y S
YS
Jolley
W B
WB
Revankar
G R
GR
Robins
R K
RK
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008934:Mitogens; D008970:Molecular Weight; D010835:Phytohemagglutinins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; D003524:Cyclosporins; D008934:Mitogens; D010835:Phytohemagglutinins; D006147:Guanine; C046220:3-deaza-2'-deoxyguanosine; C010567:3-deazaguanine; D003849:Deoxyguanosine