Failure of low-dose recombinant human IL-2 to support the survival of virus-specific CTL clones infused into severe combined immunodeficient foals: lack of correlation between in vitro activity and in vivo efficacy.
Although CTL are important for control of lentiviruses, including equine infectious anemia virus (EIAV), it is not known if CTL can limit lentiviral replication in the absence of CD4 help and neutralizing antibody. Adoptive transfer of EIAV-specific CTL clones into severe combined immunodeficient (SCID) foals could resolve this issue, but it is not known whether exogenous IL-2 administration is sufficient to support the engraftment and proliferation of CTL clones infused into immunodeficient horses. To address this question we adoptively transferred EIAV Rev-specific CTL clones into four EIAV-challenged SCID foals, concurrent with low-dose aldesleukin (180,000U/m2), a modified recombinant human IL-2 (rhuIL-2) product. The dose was calculated based on the specific activity on equine PBMC in vitro, and resulted in plasma concentrations considered sufficient to saturate high affinity IL-2 receptors in humans. Despite specific activity on equine PBMC that was equivalent to recombinant equine IL-2 and another form of rhuIL-2, aldesleukin did not support the engraftment and expansion of infused CTL clones, and control of viral load and clinical disease did not occur. It was concluded that survival of Rev-specific CTL clones infused into EIAV-challenged SCID foals was not enhanced by aldesleukin at the doses used in this study, and that in vitro specific activity did not correlate with in vivo efficacy. Successful adoptive immunotherapy with CTL clones in immunodeficient horses will likely require higher doses of rhuIL-2, co-infusion of CD4+ T lymphocytes, or administration of equine IL-2.
Mealey
Robert H
RH
Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington 99164-7040, United States. rhm@vetmed.wsu.edu
Littke
Matt H
MH
Leib
Steven R
SR
Davis
William C
WC
McGuire
Travis C
TC
D019264:Adoptive Transfer / Q000662:veterinary; D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D004859:Equine Infectious Anemia / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D005260:Female; D006736:Horses; D007167:Immunotherapy / Q000379:methods / Q000662:veterinary*; D004860:Infectious Anemia Virus, Equine / Q000276:immunology*; D007279:Injections, Subcutaneous / Q000662:veterinary; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000031:analogs & derivatives; D008297:Male; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology
D007376:Interleukin-2; D012367:RNA, Viral; D011994:Recombinant Proteins; C082598:aldesleukin