ROLE OF CYTOKINES IN TERMINATION OF THE B-CELL LYMPHOMA DORMANT STATEIN AKR MICE

The high incidence of spontaneous T cell lymphomas in AKR mice (affect ed by sustained viremia) can be greatly reduced by experimental manipu lations including thymus removal at young age or by genetic manipulati on changing the Fv-l allele that controls replication and spread of vi ruses (establishing the congenic AKR.Fv-1(b) mice). Although T cell ly mphomagenesis is prevented, all these mice were shown to carry endogen ous ecotropic provirus-induced potential lymphoma cells (PLCs) in a do rmant state. The termination of the dormant state, leading to a high i ncidence of CD5(+) IgM(+) B cell lymphomas, was triggered by interfere nce with T cell functions (optimal effect observed following in vivo a dministration of anti-CD8 moAb), administration of T cell growth facto rs or by injecting the MCF-247 recombinant virus isolate (from AKR ori gin) that affects T cell functions. The assumption that the PLC dorman t state is maintained through specific immunological mechanisms (invol ving T cells or antibodies recognizing PLCs) could not be substantiate d experimentally. The results of the present studies suggest that T ce lls provide immunoregulatory signals or factors that contribute to the maintenance of the B cell lymphoma arrest and/or proliferation. Analy sis of cytokine levels produced by splenocytes taken from mice during PLC dormancy or its breakdown indicated reduced levels of IL-2 and IL- 4 and marked elevation of IL-1 and IL-6 associated with the terminatio n of the dormant state. The effect of IL-1 and IL-6 on terminating the dormant state was demonstrated by injecting these cytokines into PLC carriers, thymectomized 12-month-old AKR mice, yielding 80-85% CD5(+) IgM(+) B cell lymphomas. The role of IL-6 on B cell lymphoma prolifera tion was also indicated in MCF-247 mediated termination of dormancy, b y inhibiting significantly its effect via in vivo administration of an ti IL-6 moAbs.