Immunomodulatory Effects of Anti-CD4 Antibody in Host Resistance against Infections and Tumors in Human CD4 Transgenic Mice
Open Access
- 1 February 2001
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 69 (2), 1032-1043
- https://doi.org/10.1128/iai.69.2.1032-1043.2001
Abstract
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 cariniiand anti-Candida albicansantibody responses and rendered HuCD4/Tg mice susceptible toP. carinii, a CD4-dependent pathogen, but did not compromise host defense againstC. albicansinfection. 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.Keywords
This publication has 53 references indexed in Scilit:
- Inhibition of contact sensitivity in human CD4+ transgenic mice by human CD4‐specific monoclonal antibodies: CD4+ T‐cell depletion is not requiredImmunology, 2000
- ImmunocytokinesPharmacology & Therapeutics, 1998
- A PrimatizedMAb to Human CD4 Causes Receptor Modulation, without Marked Reduction in CD4+T Cells in Chimpanzees:In Vitroandin VivoCharacterization of a MAb (IDEC-CE9.1) to Human CD4Clinical Immunology and Immunopathology, 1997
- Single-Organism Model of Host Defense against Infection: A Novel Immunotoxicologic Approach to Evaluate Immunomodulatory DrugsToxicologic Pathology, 1997
- Anti-β1Integrin IgG Inhibits Pulmonary Macrometastasis and the Size of Micrometastases from a Murine Mammary CarcinomaCell Adhesion and Communication, 1994
- Age Influences Recovery of Systemic and Mucosal Immune Responses Following Acute Depletion of CD4 T CellsClinical Immunology and Immunopathology, 1993
- Treatment of rheumatoid arthritis with an anti‐CD4 monoclonal antibodyArthritis & Rheumatism, 1991
- TH1 and TH2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional PropertiesAnnual Review of Immunology, 1989
- Cell adhesion and experimental metastasis: a study using the B16 malignant melanoma model systemEuropean Journal of Cancer and Clinical Oncology, 1984
- Specific suppression of responses to Leishmania tropica by a cloned T-cell lineNature, 1983