Low doses of IL-4 injected perilymphatically in tumor-bearing mice inhibit the growth of poorly and apparently nonimmunogenic tumors and induce a tumor-specific immune memory.
The ability of rIL-4 to trigger host reactivity against both a chemically induced fibrosarcoma (CE-2) and a spontaneous adenocarcinoma (TS/A) of BALB/c mice was studied. Daily local s.c. administration around tumor draining lymph nodes of 10 injections of progressive amounts (0.00001 to 1000 pg/day) of rIL-4 induced appreciable inhibition of the growth of both tumors after a dose-response survival curve peaking at 0.1 pg/day. Inasmuch as rIL-4 has no direct antitumor activity, as shown by in vitro tests, host immune reactivity plays a fundamental role in this lymphokine activated tumor inhibition (LATI). LATI, in fact, is abolished when recipient mice are sublethally irradiated or treated with cyclosporin A, or when the reactivity of CD4+ lymphocytes is suppressed, whereas it is not affected by anti-asialo GM1 antibody. The morphologic data show that rIL-4 LATI rests on the recruitment of several cell reaction mechanisms, among which those that are nonspecific seem to predominate. rIL-4 LATI also leads to a state of long lasting and specific immune memory: the growth of a second contralateral tumor challenge is significantly impaired after LATI. This immune memory takes place after LATI of both the poorly immunogenic CE-2 fibrosarcoma and the TS/A adenocarcinoma, previously classed as nonimmunogenic on the basis of immunization-protection tests. In the latter case, adoptive transfer experiments show that Thy-1+ lymphocytes and, in particular, the CD4 cell-depleted T lymphocyte subpopulation, are responsible for the immune memory. Finally, the ability of rIL-4 to trigger LATI is greater than that of the most effective doses of rIL-2, rIL-1 beta, and IFN-gamma, whereas its association with rIL-1 beta induces a more effective immune memory.
Institute of Microbiology, University of Turin, Italy.
M
M
Bosco
M
M
Giovarelli
M
M
Forni
A
A
Modesti
S
S
Scarpa
L
L
Masuelli
G
G
Forni
D000230:Adenocarcinoma / Q000276:immunology; D000276:Adjuvants, Immunologic; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007111:Immunity, Cellular; D007116:Immunization, Passive; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D015847:Interleukin-4 / Q000008:administration & dosage*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008854:Microscopy, Electron; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins; D012513:Sarcoma, Experimental / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*
D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D015847:Interleukin-4