Search

The envelope protein gp120, part of the outer layer of the human immunodeficiency virus (HIV), can be different in various strains of the virus. Differences can occur within strains isolated from separate individuals and can even occur within different isolates from the same individual. Understanding the genetic variability is important as the gp120 protein is involved in cell-mediated immunity against HIV-infected cells, and this variability has allowed the virus to evade immune responses by the individual. The envelope protein gp120 has been the prime target in vaccine development, but its genetic variability has complicated this research. The envelope protein of the virus is processed and forms a complex with molecules known as the major histocompatibility complex (MHC). The complex then binds to a molecule, known as CD4, on T helper cells and other cells of the immune system, which stimulate the production of an immune response. Peptides (portions of proteins) of the gp120 molecule from different isolates were tested for their ability to stimulate helper T cells. If the peptides did not cause immune stimulation, the reason could be that the peptides could not form a complex with the MHC molecule, or they could form a complex, but the complex could not bind to the CD4 molecule on helper T cells. Peptides to the gp120 molecule in 12 of 14 strains tested could bind to the MHC molecule. However, in two strains, the variability in the gp120 molecules prevented the initial interaction between the gp120 and the MHC molecules. These strains were obtained from Africa and were highly divergent from the North American strains. Most of the variations still allowed the peptide to form a complex with the MHC. Therefore, many individuals can respond to a variety of gp120 molecules. In some strains, the peptide/MHC complex could be formed, but the complex could not interact with helper T cells. This indicates that, although the genetic variants of gp120 may be able to evade ongoing T cell responses, new responses will be generated. (Consumer Summary produced by Reliance Medical Information, Inc.)

Inflammatory bowel disease (IBD) is a generic term typically used to describe a group of idiopathic inflammatory intestinal conditions in humans that are generally divided into Crohn's disease and ulcerative colitis. Although the etiology of these diseases remains unknown, a number of rodent models of IBD have recently been identified, all sharing the concept that the development of chronic intestinal inflammation occurs as a consequence of alterations in the immune system that lead to a failure of normal immunoregulation in the intestine. On the basis of these models, it has been hypothesized that the development of IBD in humans may be related to a dysregulated immune response to normal flora in the gut. Immunodeficient scidmice injected with CD4+CD45RBhighT cells and mice deficient in interleukin (IL)-10 (IL-10-/-) are among the rodent models of IBD. In both models, there is inflammation and evidence of a Th1-like response in the large intestine, characterized by CD4+T-cell and macrophage infiltrates, and elevated levels of interferon-γ. Because IL-10 is an immunomodulatory cytokine that is capable of controlling Thl-like responses, the role of IL-10 was investigated in these models. IL-10 was shown to be important in regulating the development of intestinal inflammation in both models. These results provided key data that supported initiation of clinical trials evaluating the efficacy of IL-10 in patients with IBD.

Our studies have elucidated, in part, the mechanism whereby persistent stimulation by normal enteric antigens leads to the development of chronic enterocolitis in interleukin 10‐deficient (IL‐10‐/‐) mice. This disease is mediated by IL‐10‐/‐CD4+T cells as evidenced by their ability to transfer colitis to immunodeficient RAG‐2‐/‐mice. Furthermore, the CD4+T cells recovered from the affected colons of IL‐10‐/‐mice consisted of a highly polarized Th1‐like population because they produced interferon‐γ (IFN‐γ) but not IL‐4. We found that enterocolitis could be prevented if 3‐week‐old mutants were treated for 6–8 weeks with either anti‐IL‐12 or anti‐IFN‐γ monoclonal antibodies (mAb). These results were consistent with the findings of in vitro studies suggesting that IFN‐γ and, in particular, IL‐12 direct the differentiation of naive T cells toward a Th1 phenotype. Apparently, the uncontrolled production of IL‐12 and IFN‐γ by accessory cells and T cells, respectively, in IL‐10‐/‐mice ultimately resulted in the excessive generation and activation of Th1 cells, hence, immunopathology. IL‐10‐/‐mice have also been used to evaluate the importance of IL‐10 in regulating immune responses outside of the gastrointestinal (GI) tract. In these studies, IL‐10‐/‐mice were challenged with a variety of foreign antigens using different routes of administration. In general, the results repeatedly demonstrated that a major function of IL‐10 is to protect the host from the harmful side effects of an overly zealous immuneinflammatory response. However, other studies have confirmed speculations that the potent immunosuppressive activities of IL‐10 may, under certain circumstances, increase the host's susceptibility to infection with certain types of pathogenic organisms. J. Leukoc. Biol. 61: 389–396; 1997.

Positive selection of T lymphocytes expressing self-MHC-restricted T cell receptors is mediated by MHC molecules expressed on thymic stroma. Among the more controversial aspects of this process is the relative role of MHC molecules on epithelial versus bone marrow-derived stromal elements (BM-APC). For CD4+T cells, the weight of evidence suggests that positive selection is driven solely by MHC class II molecules expressed on thymic epithelial cells. In contrast, recent experiments have been interpreted to show that CD8+T cell development can be driven by MHC class I molecules expressed on BM-APCs as well as epithelial cells. To directly address this issue, we have examined the development of T cells expressing a transgenic MHC class I-restricted TCR in mice deficient in the rearrangement of endogenous TCR genes. Since the transgenic TCR is the only TCR expressed, this system is extremely sensitive and specific for detecting even inefficient events in T cell development. Our experiments demonstrate that MHC class I expression exclusively on BM-APC is incapable of driving positive selection of CD8+T cells. This finding, together with earlier experiments for MHC class II, suggests a qualitatively unique function of thymic epithelial cells in mediating positive selection.