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 a nti-ICAM-1 monoclonal antibodies (MAbs) in the immune reaction to Molo ney-murine-sarcoma-virus(M-MSV)-induced tumors, which spontaneously re gress due to the generation of a strong virus-specific cytotoxic-T-lym phocyte(CTL) response. Repeated systemic administration of both MAbs t o M-MSV-injected mice enhanced tumor growth and delayed regression, wh ile treatment with a single MAb had a similar, though less pronounced, effect. The immune depression achieved could not be attributed to lym phocyte depletion, because no reduction in the total number of leukocy tes was detected in the peripheral blood or spleen of these mice. Howe ver, anti-LFA-1 MAb, alone or in combination with anti-ICAM-1 MAb, pre vented lymphocyte homing in tumor-draining lymph nodes. Cytofluorimetr ic analysis disclosed a profound down-modulation of LFA-1 and ICAM-1 m olecule expression on T cells following in vivo MAb treatment. Moreove r, in anti-LFA-1 MAb-treated mice, the receptor was coated to saturati on, while anti-ICAM-1 MAb treatment brought about ICAM-1-molecule-coat ing levels below saturation. Evaluation of M-MSV-specific CTL precurso r (p) frequency in lymphoid organs of mice receiving combined MAb trea tment showed that CTL generation was greatly reduced 10 days after M-M SV injection, and day returned to control levels by day 15. Our findin gs indicate that systemic administration of MAbs to LFA-1 and ICAM-1 m olecules brings about a strong immune suppressive effect which is main ly due to a block in T-lymphocyte re-circulation, and activation by tu mor cells. However, this immune-depressive effect is only temporary, a nd strictly dependent on continuous MAb administration. Thus, our data suggest that treatment with anti-LFA-1 and anti-ICAM-1 MAbs combined is unable to induce T-cell tolerance in a highly immunogenic system. ( C) 1995 Wiley-Liss, Inc.