Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human CD4+ T cell clones infected in vitro with the human immunodeficiency virus (HIV), unlike their noninfected counterparts, induced both proliferation and immunoglobulin (Ig) production by both autologous and allogeneic B cells through an antigen (Ag)-nonspecific, MHC-unrestricted, contact-dependent mechanism. This was done apparently without expressing the CD40 ligand. Interestingly, HIV-infected T cell clones, unlike their noninfected counterparts, constitutively expressed mRNA for, and released in the supernatants measurable amounts of, TNF-alpha and a proportion of T blasts from the HIV-infected unstimulated T cell clones showed membrane TNF-alpha expression. Furthermore, both B cell proliferation and Ig production induced by HIV-infected unstimulated T cell clones, but not those evoked by their noninfected anti-CD3-stimulated counterparts, were strongly and consistently inhibited by either anti-TNF-alpha or anti-TNF-alpha receptor antibodies. Finally, when T blasts from HIV-infected unstimulated T cell clones were fractionated by cell sorting into membrane TNF-alpha-negative and membrane TNF-alpha-positive cells, only the latter retained the capacity to polyclonally activate B cells. Human CD4+ T cell clones infected in vitro with herpesvirus saimiri (HVS) also showed constitutive membrane TNF-alpha expression, as well as the ability to induce Ag-nonspecific, MHC-unrestricted, contact-dependent, polyclonal B cell activation. These data suggest that human CD4+ T cell clones, when infected by certain viruses, can provide abnormal B cell help that appears to be related to the expression of membrane TNF-alpha by virus-infected T cells.
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PMID:Abnormal B cell helper activity by virus-infected human CD4+ T cells. 812 98

The protection against infection by HIV probably requires the induction of both neutralizing Abs and CTL responses. Vaccination by attenuated HIV is hardly acceptable and the use of viral genes inserted in recombinant living vectors needs further development, especially with respect to safety. The peptidic vaccination is a promising approach but free peptides are usually poorly immunogenic. Because potent immune responses have been obtained in mice with modified peptides such as lipopeptides, we have designed a study to assess the immunogenicity of lipopeptides in nonhuman primates. Seven lipopeptides were synthesized, derived from known immunogenic regions of the simian immunodeficiency virus (SIV) NEF and GAG proteins. Twelve rhesus macaques, randomly chosen and not selected on their MHC basis, were immunized subcutaneously with the seven lipopeptides in IFA. An MHC class I-restricted and CD(8+)-mediated CTL response has been observed in seven macaques directed against one or two of the synthetic immunizing peptides in each case. These CTLs were able to lyse autologous target cells infected with a recombinant vaccinia virus expressing the SIV nef or gag genes, suggesting that they recognized the naturally processed peptides. These activities are detectable in peripheral blood cells for at least 10 mo after the last immunization. Abs against the immunizing peptides have also been observed in all cases. This study demonstrates that lipopeptides can generate cytotoxic and humoral immune responses in a large number of unselected animals and this approach may thus be worth considering in the vaccination against HIV.
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PMID:Simian immunodeficiency virus as a model for vaccination against HIV. Induction in rhesus macaques of GAG- or NEF-specific cytotoxic T lymphocytes by lipopeptides. 813 61

Inbred strains of mice differ markedly in their relative susceptibility to the development of lymphoproliferation and immunodeficiency, a syndrome termed mouse AIDS (MAIDS), after infection with the LP-BM5 mixture of murine leukemia viruses (MuLV). The etiologic virus in this mixture is replication defective (BM5def) and encodes only a variant gag protein. Genetic determinants of resistance and susceptibility to induction of MAIDS reside both within and outside the MHC. In strains with C57BL background genes, the MHC haplotypes associated with resistance to disease include d and a, whereas haplotypes b, s, and q are associated with sensitivity. Previous studies showed that MHC class I genes (H-2Dd, H-2Ld) mapping in the D end of H-2 and other genes mapping proximal to the D end determine resistance to MAIDS. This paper examines the nature of these non-D end MHC genes using assays of MHC recombinant and transgenic mice. We demonstrate that expression of E alpha d confers significant resistance to MAIDS, even in mice that do not express H-2Dd/H-2Ld. Unexpectedly, we found that E alpha polymorphisms can significantly influence resistance, with H-2b mice bearing E alpha d as a transgene having greater resistance to MAIDS than mice bearing an E alpha k transgene. E alpha d-mediated resistance to MAIDS was associated with decreased levels of the BM5def genome in splenic DNA, suggesting that E alpha genes exert their effect by enhancing antiviral activity.
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PMID:Influence of H-2 class II antigens on the development of murine AIDS. 814 77

CD4, a cell-surface glycoprotein expressed on a subpopulation of T cells, is the receptor for class II molecules of the major histocompatibility complex (MHC II) and a receptor for the envelope glycoprotein (gp 120) of human immunodeficiency virus-1 (HIV-1). Screening of microbial metabolites for CD4-binding activity using an enzyme-linked immunosorbent assay based on the binding of the CD4-specific monoclonal antibody (mAb), anti-Leu3a, identified a family of compounds comprising several novel polyketides. The parent compound (411F, Vinaxanthone) is a C28 molecule probably arising from a dimerization of two C14 polyketide units. It strongly inhibited the interaction of anti-Leu 3a and that of several other D1/D2 epitope-specific mAb with CD4, but only weakly inhibited the binding of HIV-1 gp120. Binding of a representative MHC class II molecule, HLA-DRB*0401, was also inhibited by 411F with a comparable inhibitory concentration (IC50 = 1 microM). In functional assays 411F inhibited antigen-induced CD4-dependent T cell proliferative responses of peripheral blood mononuclear cells. At the clonal level 411F exhibited selectivity in that the compound inhibited peptide-induced CD4+ T cell proliferative responses but not alloantigen-induced CD8+ T cell proliferation. It is hypothesized that 411F, a polyanionic compound in aqueous solution at neutral pH, inhibits CD4-dependent functions by binding over a broad area of the positively charged amino-terminal D1 and D2 domains implicated in the interaction with MHC II molecules. 411F has the potential for development as an immunosuppressive agent with a novel mechanism of action.
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PMID:A fungal metabolite which inhibits the interaction of CD4 with major histocompatibility complex-encoded class II molecules. 814 67

Allogenic diseases induced in rodents by the inoculation of foreign lymphocytes represent useful models to investigate the mechanisms governing the activation of autoreactive B cells in systemic lupus erythematosus and related autoimmune disorders. The role of CD4+ helper T cells recognizing foreign class II MHC molecules has been particularly well established in murine chronic graft-versus-host disease and host-versus-graft disease. The T cells involved in these models essentially produce interleukin-4 and interleukin-10, which corresponds to the phenotype of Th2 cells. The association between autoimmunity and cellular immunodeficiency in experimental allogenic diseases could therefore be directly related to the hyperactivity of Th2 cells. Similar mechanisms might be operative in human systemic autoimmune diseases as well as in other clinical settings such as graft-versus-host disease after bone marrow transplantation or the acquired immunodeficiency syndrome.
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PMID:[Allogenic reaction, a model of autoimmunity]. 817 59

SIVsmmPBJ 1.9 is an extremely virulent clone of the simian immunodeficiency virus SIVsmmPBj 14 that causes an acute lethal disease in pigtail macaques, with death occurring 6 to 8 days after infection. The disease is characterized by bloody mucoid diarrhea, lymphoid hyperplasia, and giant cell pneumonia. We have developed an in vitro model for the production of multinucleated giant cells (MGCs) in which peripheral blood monocytes rapidly fuse to form MGCs when cultured in lymphocyte-conditioned medium and antibody against class II MHC. We have tested the effect of SIVsmmPBj on monocytes in our MGC model system. Peripheral blood mononuclear cells (PBMCs) from normal healthy human subjects, when cultured in the presence of anti-class II MHC monoclonal antibody and SIVsmmPBj 1.9, but not either alone, resulted in the formation of MGCs within 4 days. Experiments using Transwell chambers indicated that such MGCs are formed by fusion of monocytes, not by virus-induced fusion of lymphocytes. SIVsmmPBj 1.9 is unique in inducing MGC formation in that other SIV and HIV isolates do not induce MGCs. Whereas SIVsmmPBj 1.9 grown in PBMCs was a potent inducer of MGCs in the presence of anti-class II MHC antibody, SIVsmmPBj 1.9 grown in CEMx174 failed to do so. Antibodies against IFN-gamma and TNF-alpha significantly inhibited SIVsmmPBj/anti-class II-induced formation of MGCs. These results indicate that cytokines released in response to SIVsmmPBj 1.9, in conjunction with antibodies to class II MHC, caused fusion of monocytes.
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PMID:Simian immunodeficiency virus SIVsmmPBj 1.9 induces multinucleated giant cell formation in human peripheral blood monocytes. 817 65

Vaccine therapy studies in HIV-seropositive volunteers over the next year should provide additional insights into whether different vaccine viral strains (LAI, IIIB, MN, SF2), different protein sources (whole virus particles, recombinant protein, peptides), different expression systems (baculovirus, mammalian), or different adjuvants (incomplete Freund's, MTP-PE, MF59, alum) generate significantly different immune responses at the cellular and humoral level. In addition, differences in the ability of each vaccine to induce humoral immune responses to epitopes in the constant regions vs. variable regions, contiguous or noncontiguous "conformational" epitopes, with high vs. low antibody affinity can be evaluated. The roles of antibody-dependent cellular cytotoxicity (ADCC), cellular recognition, nonspecific natural killing, and MHC-restricted cytotoxicity can also be explored. To date, the majority of the immunogens have proven to be safe. Many induce new humoral and cellular immune responses against HIV. The final important question remains, whether any of these vaccines used as therapeutic immunogens generate immune responses that induce an altered disease course with a prolonged asymptomatic period without immunodeficiency, whether vaccines can affect increased viral clearance, or decreased transmission/infectivity? There remains no in vitro assay known to correlate with lack of disease progression, no immune profile consistent with a prolonged asymptomatic period. The vaccine therapy trial researchers seek the answers to these important questions. No single research organization can begin to address all the possibilities, so the overall pace of exploration of this therapeutic concept is likely to be dictated by the level of cooperation between the many groups involved in these studies. Open collaboration between researchers and open exchange of reagents, immunogens for in vitro experiments, and sera will allow faster dissection of the many questions and issues raised in this chapter. Whether vaccine therapy proves to have a useful role in the treatment of HIV-1-induced disease, these studies will ultimately lead to the development of useful techniques and provide new insights into the nature of the immunological responses, as the investigation of vaccine therapy did over a century ago.
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PMID:Vaccines directed against HIV: preventive and therapeutic strategies. 821

Susceptibility to collagen-induced arthritis (CIA) in mice is associated with a class II gene in MHC (Aq) but also with unknown genes outside MHC. Investigated here is the influence of genes on the X chromosome as well as the role of the X-linked immunodeficiency (xid) mutation. Reciprocal male F1 hybrids, bred to be heterozygous or homozygous for Aq, showed a genetic influence in their susceptibility to develop CIA. Crosses were made between B10.G, B10.Q, DBA/1, SWR/J, C3H.Q and CBA/Ca, and all F1 mice were castrated to avoid sex hormone modulation of the susceptibility. A differential timing of arthritis onset and severity were seen in the reciprocal F1 males. An exception was the reciprocal F1 male offspring from SWR/J and DBA/1 crosses which differed only in disease severity late in the course of the disease. The female F1 crosses did not show the same pattern of differential susceptibility to CIA as the F1 males. To exclude the possible influence of the Y chromosome, F1 males of reciprocal crosses were back-crossed to the parental strains creating offspring with equal X chromosomes but divergent Y chromosomes. No difference in development of arthritis was observed in these. The influence of the xid mutation was investigated next. The xid loci from the CBA/N mouse was bred into DBA/1 strain which is highly susceptible to CIA. The resulting congenic DBA/1-xid strain was resistant to induction of CIA and did not develop an antibody response to type II collagen. We conclude that polymorphic genes on the X chromosome modulate susceptibility to CIA. The results from the experiments with mice carrying xid mutations confirm that such immune modulating genes exist on the sex chromosomes.
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PMID:Genes on the X chromosome affect development of collagen-induced arthritis in mice. 825 7

The role of TNF in the expression of GVHD and GVHD-related immunodeficiency was studied in a well-established murine GVHD model of bone marrow transplantation across minor histocompatibility barriers (B10.BR-->GBA/J) both in vitro and in vivo. Splenocytes from animals with GVHD profoundly inhibited the proliferation of normal spleen cells in response to a wide range of stimuli in an MHC-nonrestricted fashion. Neutralizing mAbs to TNF reversed the ability of splenocytes from animals with GVHD to suppress the proliferation of normal splenocytes stimulated by the mitogen concanavalin A. Addition of rTNF enhanced the degree of suppression. This reversal was similar to that previously reported for IFN gamma and leucine methyl ester treatment of the GVHD populations. All three components are necessary for suppression to occur because addition of rTNF to cultures in which suppression had been reversed by anti-IFN gamma or leucine methyl ester treatment did not reconstitute suppression. Neutralization of endogenous TNF production in vivo resulted in an amelioration of clinical GVHD, but neutralization of endogenous IFN gamma resulted in a more severe course. However, in vivo neutralization of either TNF or IFN gamma post-BMT resulted in a decreased ability of splenocytes from animals with GVHD to suppress mitogen responses but did not affect the generation of the suppressor cell population. These findings support multiple roles for TNF and IFN gamma in the pathophysiology of GVHD, including terminal cellular differentiation and/or regulation of effector cell function.
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PMID:The role of tumor necrosis factor and interferon gamma in graft-versus-host disease and related immunodeficiency. 831 May 20

In the past few years, there has been a virtual explosion of information on the viral and bacterial molecules now known as superantigens. Some structures have been defined and the mechanism by which they interact with MHC class II and the V beta region of the T cell receptor is being clarified. Data are accumulating regarding the importance of virally encoded superantigens in infectivity, viral replication, and the life cycle of the virus. In the case of MMTV, evidence also suggests that superantigens encoded by a provirus may be maintained by the host to protect against future exogenous MMTV infection. Experiments in animals have also begun to elucidate the dramatic and variable effects of superantigens on responding T cells and other immune processes. Finally, the role of superantigens in certain human diseases such as toxic shock syndrome, some autoimmune diseases like Kawasaki syndrome, and perhaps some immunodeficiency disease such as that secondary to HIV infection is being addressed and mechanisms are being defined. Still, numerous important questions remain. For example, it is not clear how superantigens with such different structures, for example, SEB, TSST-1, and MMTV vSAG, can interact with MHC and a similar region of the TCR in such basically similar ways. It remains to be determined whether there are human equivalents of the endogenous murine MMTV superantigens. The functional role of bacterial superantigens also remains to be explained. Serious infection and serious consequences from toxin-producing bacteria are relatively rare events, and it is questionable whether such events are involved in the selection pressure to maintain production of a functional superantigen. Hypotheses to explain these molecules, which can differ greatly in structure, include T cell stimulation-mediated suppression of host responses or enhancement of environments for bacterial growth and replication, but substantiating data for these ideas are mostly absent. It also seems likely that only the tip of the iceberg has been uncovered in terms of the role of superantigens in human disease. Unlike toxic shock syndrome, other associations, especially with viral superantigens, may be quite subtle and defined only after considerable effort. The definition of these molecules and mechanisms of disease may result in new therapeutic strategies. Finally, it is apparent that superantigens have dramatic effects on the immune system. One wonders whether these molecules or modifications of them can be used as specific modulators of the immune system to treat disease.
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PMID:Superantigens and their potential role in human disease. 839 79


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