Role of anti-LFA-1 and anti-ICAM-1 combined MAb treatment in the rejection of tumors induced by Moloney murine sarcoma virus (M-MSV).
We investigated the effect of combined treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies (MAbs) in the immune reaction to Moloney-murine-sarcoma-virus(M-MSV)-induced tumors, which spontaneously regress due to the generation of a strong virus-specific cytotoxic-T-lymphocyte(CTL) response. Repeated systemic administration of both MAbs to M-MSV-injected mice enhanced tumor growth and delayed regression, while treatment with a single MAb had a similar, though less pronounced, effect. The immune depression achieved could not be attributed to lymphocyte depletion, because no reduction in the total number of leukocytes was detected in the peripheral blood or spleen of these mice. However, anti-LFA-I MAb, alone or in combination with anti-ICAM-I MAb, prevented lymphocyte homing in tumor-draining lymph nodes. Cytofluorimetric analysis disclosed a profound down-modulation of LFA-I and ICAM-I molecule expression on T cells following in vivo MAb treatment. Moreover, in anti-LFA-I MAb-treated mice, the receptor was coated to saturation, while anti-ICAM-I MAb treatment brought about ICAM-I-molecule-coating levels below saturation. Evaluation of M-MSV-specific CTL precursor (p) frequency in lymphoid organs of mice receiving combined MAb treatment showed that CTL generation was greatly reduced 10 days after M-MSV injection, and returned to control levels by day 15. Our findings indicate that systemic administration of MAbs to LFA-I and ICAM-I molecules brings about a strong immune suppressive effect which is mainly due to a block in T-lymphocyte re-circulation, and activation by tumor cells. However, this immune-depressive effect is only temporary, and strictly dependent on continuous MAb administration. Thus, our data suggest that treatment with anti-LFA-I and anti-ICAM-I MAbs combined is unable to induce T-cell tolerance in a highly immunogenic system.
Rosato
A
A
Institute of Oncology, University of Padua, Italy.
Mandruzzato
S
S
Bronte
V
V
Zambon
A
A
Macino
B
B
Calderazzo
F
F
Zanovello
P
P
Collavo
D
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology*; D007958:Leukocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008980:Moloney murine sarcoma virus; D012192:Retroviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D012513:Sarcoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014412:Tumor Virus Infections / Q000276:immunology / Q000517:prevention & control / Q000628:therapy
D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1