Heinzel F P, Sadick M D, Holady B J, Coffman R L, Locksley R M

Heinzel F P, Sadick M D, Holady B J, Coffman R L, Locksley R M. Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of HLCL-61 keliximab. This was further demonstrated from the differential effect of keliximab on type 1 and type 2 cytokine manifestation in splenocytes stimulated ex lover vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation HLCL-61 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. Consequently, keliximab therapy may be beneficial in controlling particular autoimmune diseases. Immunity against different microorganisms entails specialized types of sponsor responses which identify, control, and get rid of infectious agents. The majority of microbial antigens are endocytosed by antigen-presenting cells (APC), including macrophages, dendritic cells, and B lymphocytes, to be processed and presented to T lymphocytes. T lymphocytes identify antigens indicated on the surface of target cells in association with either class I major histocompatibility complex (MHC) molecules or class II MHC molecules, leading to the activation of CD8+ class I MHC-restricted cytotoxic T cells or CD4+ class II MHC-restricted T-helper cells, respectively. Activation of CD4+ T cells is definitely regulated from the CD4 surface molecule by participating in the T-cell receptor (TCR)-MHC II antigen acknowledgement process (6, 9). Activated CD4+ T-helper (Th) cells provide help to B lymphocytes for the production of antibodies against microbial antigens, which is definitely controlled by multiple cytokines that regulate cellular relationships and promote effector cell activities. T-cell responses belong to either the Th1 type, dominated from the production of gamma interferon (IFN-) and associated with cell-mediated immunity, or the Th2 type, distinguished from the production of interleukin-4 (IL-4) and associated with humoral immunity (38). Many other cytokines are involved in the polarization of the immune response; primarily, tumor necrosis element alpha, IL-2, and IL-12 are related to the Th1 type, while IL-5 and IL-10 are linked with Rabbit polyclonal to ACCS the Th2 phenotype. The characterization of the type of immune response provides a basis for understanding how T cells contribute to resistance or susceptibility to different infections. CD4+ T cells will also be involved in the pathogenesis of multiple autoimmune diseases, which happen when tolerance to self HLCL-61 antigens breaks down, by fostering HLCL-61 HLCL-61 and aggravating inflammatory conditions. Therefore, antibodies against CD4 that block activation of CD4+ T cells have been evaluated in animal models of autoimmune diseases and shown to inhibit disease onset and/or progression (37, 39, 51). In addition to studies in animal models, anti-human CD4 antibodies have been used experimentally in human being medical tests for the treatment of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and insulin-dependent diabetes mellitus (19, 26, 27, 32). One such antibody is definitely keliximab (IDEC CE9.1/SB-210396), a Primatized chimeric (macaque variable and human being constant areas, IgG1 lambda) monoclonal anti-CD4 antibody expressed in CHO cells (1). It is specific for human being and chimpanzee CD4 and for CD4 in transgenic mice which communicate human being CD4 (murine CD4 knockout, human being CD4 knockin [HuCD4/Tg]) (29). Treatment of HuCD4/Tg mice with keliximab in the epicutaneous sensitization model caused inhibition of contact sensitivity, indicating an effective connection between human being CD4 and keliximab in an in vivo system (41). Cells expressing human being CD4 in HuCD4/Tg mice reside in T-cell regions of all lymphoid organs and also on dendritic and Langerhans cells and macrophages. The distribution of additional murine T lymphocytes (CD3+, CD8+) and B lymphocytes (CD45R+) was not affected during the generation of these mice (29). The biologic activity of human being CD4 in HuCD4/Tg mice has been characterized in terms of immune function and sponsor defense. Peripheral CD4+ T cells in HuCD4/Tg mice have a similar memory-to-na?ve percentage to that of BALB/c CD4+ T cells, indicating normal in vivo T-cell maturation. Furthermore, TCR-CD4-mediated signaling in HuCD4/Tg and BALB/c CD4+ T cells is similar, demonstrating that the appropriate murine tyrosine kinase signaling molecules can associate with the human being CD4 transgene product (our unpublished results). HuCD4/Tg mice manifest normal T-cell-dependent humoral and cellular immune responses, including a healthy host defense against and infections. HuCD4/Tg mice have survived for 18 to 24 months in our facilities with no unpredicted pathologic developments. Taken together, results from in vivo and in vitro assessments show that insertion of the human being CD4 transgene into murine T cells following a disruption of murine CD4.