Immunomodulatory effects of anti-CD4 antibody in host resistance against infections and tumors in human CD4 transgenic mice.
Anti-CD4 antibodies, which cause CD4(+) T-cell depletion, have been shown to increase susceptibility to infections in mice. Thus, development of anti-CD4 antibodies for clinical use raises potential concerns about suppression of host defense mechanisms against pathogens and tumors. The anti-human CD4 antibody keliximab, which binds only human and chimpanzee CD4, has been evaluated in host defense models using murine CD4 knockout-human CD4 transgenic (HuCD4/Tg) mice. In these mice, depletion of CD4(+) T cells by keliximab was associated with inhibition of anti-Pneumocystis carinii and anti-Candida albicans antibody responses and rendered HuCD4/Tg mice susceptible to P. carinii, a CD4-dependent pathogen, but did not compromise host defense against C. albicans infection. Treatment of HuCD4/Tg mice with corticosteroids impaired host immune responses and decreased survival for both infections. Resistance to experimental B16 melanoma metastases was not affected by treatment with keliximab, in contrast to an increase in tumor colonization caused by anti-T cell Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of keliximab. This was further demonstrated by the differential effect of keliximab on type 1 and type 2 cytokine expression in splenocytes stimulated ex vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation of IL-4 and IL-10. Taken together, the effects of keliximab in HuCD4/Tg mice suggest that in addition to depleting circulating CD4(+) T lymphocytes, keliximab has the capability of modulating the function of the remaining cells without causing general immunosuppression. Therefore, keliximab therapy may be beneficial in controlling certain autoimmune diseases.
Herzyk
D J
DJ
Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Danuta_J_Herzyk@sbphrd.com
Gore
E R
ER
Polsky
R
R
Nadwodny
K L
KL
Maier
C C
CC
Liu
S
S
Hart
T K
TK
Harmsen
A G
AG
Bugelski
P J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000502:physiology*; D002177:Candidiasis / Q000276:immunology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000556:secondary*; D051379:Mice; D008822:Mice, Transgenic; D016720:Pneumocystis Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007166:Immunosuppressive Agents; C121251:keliximab