Effect of interferon or Propionibacterium acnes on the course of experimentally induced feline infectious peritonitis in specific-pathogen-free and random-source cats.

Seventy-four cats (52 treated and 22 untreated) were evaluated in efficacy studies of interferon (IFN), Propionibacterium acnes, or a combination of these drugs against experimentally induced feline infectious peritonitis (FIP). Cats were given doses of recombinant human leukocyte (alpha) IFN (rHuIFN-alpha), feline fibroblastic (beta) IFN (FIFN-beta) or P acnes at regular intervals before and after inoculation of virulent FIP virus (FIPV). Prophylactic and therapeutic administration of high doses (10(6) U/kg of body weight) or moderate doses (10(4) U/kg) of rHuIFN-alpha, FIFN-beta (10(3) u/kg), or P acnes (0.4 or 4 mg) did not significantly reduce mortality in treated vs untreated cats. However, the mean survival time in cats treated with 10(6) U of rHuIFN-alpha-/kg alone or combined with doses of P acnes was significantly (P = 0.03) increased after inoculation of highly lethal amounts (200 LD100) of FIPV vs survival time in untreated cats. Although P acnes alone was ineffective, there was some indication that a combination of P acnes and high doses of rHuIFN-alpha was more effective than rHuIFN-alpha alone. Seemingly, the efficacy of rHuIFn-alpha treatment was improved in cats challenge-exposed with less FIPV; in 1 trial, 4 of 5 cats (80%) treated with high doses of rHuIFN-alpha survived after inoculation of minimal lethal amounts (0.6 LD100) of FIPV, whereas only 2 of 5 untreated cats (40%) survived. Pretreatment of cats with 10(6) U of rHuIFN-alpha/kg resulted in detectable serum IFN activity 24 hours later; serum IFN activity was not detected in cats pretreated with P acnes, FIFN-beta, or 10(4) U of rHuIFn-alpha/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of recombinant human interferon-alpha in vitro and in vivo on mitogen-induced lymphocyte blastogenesis in cats.

The effect of recombinant human interferon-alpha (rHuIFN-alpha) in vitro and in vivo on mitogen-induced lymphocyte blastogenesis was evaluated in specific-pathogen-free cats. Pre-incubation of isolated feline peripheral blood lymphocytes (PBL) in vitro with either 10(4) or 10(3) International Units (U) of rHuIFN-alpha for 24 h significantly suppressed (P less than 0.001 and 0.01, respectively) blastogenic responses to the phytomitogens concanavalin A (Con A) and pokeweed mitogen (PWM). Lower doses of IFN (range, 10-10(-3) U/ml) neither suppressed nor enhanced mitogenesis. In the absence of phytomitogens, incubation of PBL with 10(4) - 10(2) U (P less than 0.001) or 10 U (P less than 0.05) of rHuIFN-alpha/ml resulted in a significant decrease in incorporation of [methyl-3H] thymidine into newly synthesized cellular DNA. Cultures of PBL exposed continuously for 4 days to rHuIFN-alpha doses of 10(4) U/ml or less did not demonstrate specific reductions in cell viability, indicating that the observed antiproliferative actions of IFN apparently were independent of any direct cytotoxic effects. To investigate the dose-response effects of rHuIFN-alpha in vivo on lymphocyte blastogenesis, individual groups of cats were evaluated on 3 consecutive days before and then 24 h after each cat was inoculated intramuscularly with either a high dose (10(6) U/kg), moderate dose (10(4) U/kg), or a relatively low dose (10(2) U/kg) of rHuIFN-alpha. Cats inoculated with 10(6) U of rHuIFN-alpha/kg had significantly reduced (P = 0.037) blastogenic responses to Con a at 24 h postinoculation compared to preinoculation values; mean PWM responses were also decreased, but this effect was not statistically significant. In contrast, inoculation of cats with either 10(4) or 10(2) U of rHuIFN-alpha/kg significantly enhanced (P = 0.05 or 0.008, respectively) Con A-induced blastogenesis and had no discernible effect on PWM responses. These findings suggest that very high doses of rHuIFN-alpha given parenterally may be associated with suppression of certain T-cell responses in cats; conversely, much lower doses may be immunoenhancing.

Inhibitory effects of ribavirin alone or combined with human alpha interferon on feline infectious peritonitis virus replication in vitro.

The antiviral activities of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide; virazole), either alone or in combination with recombinant human leukocyte (alpha) interferon (rHuIFN-alpha), were evaluated against feline infectious peritonitis virus (FIPV) in feline kidney-cell cultures. The 50% inhibitory dose (ID50) of ribavirin for uninfected, rapidly dividing cells was approximately 17 micrograms ml-1 whereas the ID50 for FIPV was 2.5 micrograms ml-1. The therapeutic index (TI) of ribavirin (i.e. the ratio of the minimum cell-toxic dose to minimum virus-inhibitory dose) was 6.8. Although a dose-dependent inhibition of viral infectivity occurred at non-toxic doses, maximum antiviral effects (greater than or equal to 4 log10 reduction in FIPV) occurred at cytotoxic doses. When low or moderate doses of ribavirin were combined with either 10 or 100 U of rHuIFN-alpha ml-1, the resulting antiviral effects were significantly greater than the sum of the observed effects from either ribavirin or rHuIFN-alpha alone. Significant synergistic interactions with rHuIFN-alpha occurred at ribavirin doses of 1, 5, 12.5 and 25 micrograms ml-1. Synergistic combinations of rHuIFN-alpha and ribavirin produced up to an 80-fold or a 200-fold relative increase in FIPV antiviral activities compared with that produced by equivalent doses, respectively, of ribavirin or rHuIFN-alpha alone. In cell growth studies, the addition of either 10 or 100 U of rHuIFN-alpha ml-1 to test doses of ribavirin did not increase the anticellular effect observed with ribavirin alone; seemingly, the potentiation of ribavirin antiviral activity by rHuIFN-alpha was independent of any additive cytotoxic effects. Potentially, synergistic combinations of the two antiviral agents in vivo may decrease the therapeutic dose of ribavirin required for inhibition of FIPV and thus reduce drug toxicity.