Reconstitution of cytolytic alloreactivity with N-[4-[(4-fluorophenyl) sulfonyl]phenyl]acetamide (CL 259,763) in animals immunocompromised by cyclophosphamide.
A novel synthetic immunopotentiator, i.e. N-[4-[(4-fluorophenyl)sulfonyl]phenyl]acetamide (CL 259,763), was investigated for its potential in reconstituting the cell-mediated immune response of animals whose immunologic system had been severely depressed by cytoreductive agents. It was demonstrated that lymphocytes from mice which had received 300 mg/kg of cyclophosphamide (CY) immediately following antigen sensitization had a reduced capability of responding to alloantigens in mixed lymphocyte culture and failed to generate effective cytolytic T-lymphocytes (CTL) capable of destroying appropriate tumor target cells in a cytotoxicity assay. However, treatment of these immunocompromised animals with CL 259,763 produced a significant restoration of alloreactivity, as evidenced by an enhancement of the CTL response. Although effective doses of CL 259,763 ranged from 20 to 300 mg/kg, the optimal effect was observed at 75 mg/kg. Findings from a time course study indicated that the maximum restoration occurred when CL 259,763 was given to mice 2-5 days after, but not before or simultaneously with, CY treatment. Both the immunoimpairment by CY and its reversal by CL 259,763 appeared not to be antigen specific. The lessened immunoreactivity of CY-treated mice was explicable by the presence of suppressor cells in their spleens. These suppressors were able to adhere to plastic and resisted treatment with anti-Thy 1.2 antibody, indicating a macrophage characteristic. Flow cytometric analysis indicated a quantitative depletion of all T-lymphocytes, including Thy-1.2(+), Lyt-1(+), Lyt-2(+) and L3T4(+) subsets in the spleens of CY-treated mice; however, a population of Mac-1(+) cells was markedly expanded.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
B S
BS
Chemotherapy Research Department, American Cyanamid Company, Lederle Laboratory, Pearl River, New York 10965.
Lumanglas
A L
AL
James
J P
JP
Kelley
K A
KA
Silva
J
J
Ruszala-Mallon
V
V
Lin
Y I
YI
Durr
F E
FE
D000276:Adjuvants, Immunologic; D000818:Animals; D002860:Chromium Radioisotopes; D003520:Cyclophosphamide / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005434:Flow Cytometry; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000166:cytology; D013450:Sulfones / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000276:Adjuvants, Immunologic; D002860:Chromium Radioisotopes; D013450:Sulfones; C048816:CL 259763; D003520:Cyclophosphamide