Characterization of a single dose methylprednisolone acetate immune suppression model using Cryptosporidium muris and Cryptosporidium parvum.
An immunosuppressive dose of methylprednisolone acetate (MPA) was compared with a non-immunosuppressive dose using Cryptosporidium oocyst production as an indicator of immunosuppression. To be classified as immunosuppressive, the dose had to satisfy five criteria. First, the dose had to abrogate normal immune defenses allowing the propagation of an organism to which the host is normally resistant, i.e. Cryptosporidium parvum in adult mice. Second, the dose had to decrease overall circulating CD4 T-lymphocyte numbers by greater than 80%. Third, the immunosuppressive dose had to prolong the infection beyond the normal infection length, and fourth, increase the severity of an active infection. Lastly, after complete recovery from a C. muris infection, immunosuppression must suppress the naturally acquired post infection immunity and allow reinfection. In mice immunosuppression with 600 mgMPA/kg lasted approximately 14 days and satisfied all five criteria. Fecal oocyst production could be perpetuated by dosing at 10-day intervals. A 200 mgMPA/kg dose transiently lowered CD4 counts by over 80%, but failed to override the naturally acquired post infection immunity or allow infection with C. parvum. The immunosuppressed blood profile consisted of an immediate sharp rise of mature segmented neutrophils combined with a severe decrease in circulating T-lymphocyte numbers. The rise and fall of neutrophils proved to be a good indicator of the severity and duration of immunosuppression. The thymus and spleen likewise contracted and then expanded in accordance with the steroid effect. The metabolism of MPA resulted in the eventual recovery of immune function signified by the cessation of C. parvum oocyst production. The recovery blood profile was associated with circulating CD8 counts near control levels, continuing 80% depression of CD4 counts and a dropping total neutrophil count. This study shows that the 600 mg/kg MPA dose is a good model for immunosuppression, which satisfies all five criteria for immunosuppression with low morbidity and low mortality.
Miller
Thomas A
TA
US Environmental Protection Agency, Cincinnati, OH 45268, USA.
Schaefer
Frank W
FW
D000818:Animals; D003457:Cryptosporidiosis / Q000276:immunology*; D003458:Cryptosporidium / Q000472:pathogenicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007958:Leukocyte Count / Q000662:veterinary; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D033661:Oocysts; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D007166:Immunosuppressive Agents; D008775:Methylprednisolone