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

The oligopeptides Arg-Lys-Asp (TP-3), Arg-Lys-Asp-Val (TP-4), and Arg-Lys-Asp-Val-Tyr (TP-5) considered as the active short fragments of thymopoietin were administered (lo mg/kg) to C57B1 mice 24 hours before the intravenous inoculation of Lewis lung tumor (LLT) cells. A substantial decrease in lung metastasis number was observed as a result of treatment with all of the three oligopeptides. TP-3, TP-4, and TP-5 treatment decreased the immunosuppressive activity of Cyclophosphamid (240 mg/kg) given 96 hours before the inoculation of LLT cells. After thymectomy, performed eight days before the LLT inoculation, only TP-3 treatment resulted in the decrease of Cyclophosphamid immunotoxicity. A stimulating effect of TP-3 on T helper cell activity is assumed. The oligopeptides TP-3, TP-4, and TP-5 are recommended for clinical trial in case of malignant tumors and immunodeficiency.
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PMID:The effect of TP-3 (Arg-Lys-Asp), TP-4 (Arg-Lys-Asp-Val), and TP-5 on the metastatic capacity of intravenously injected Lewis lung tumor cells. 333 95

Hemophilia-AIDS has been interpreted in terms of two hypotheses: the foreign-protein-AIDS hypothesis and the Human Immunodeficiency Virus (HIV)-AIDS hypothesis. The foreign-protein-AIDS hypothesis holds that proteins contaminating commercial clotting factor VIII cause immunosuppression. The foreign-protein hypothesis, but not the HIV hypothesis, correctly predicts seven characteristics of hemophilia-AIDS: 1) The increased life span of American hemophiliacs in the two decades before 1987, although 75% became infected by HIV--because factor VIII treatment, begun in the 1960s, extended their lives and simultaneously disseminated harmless HIV. After 1987 the life span of hemophiliacs appears to have decreased again, probably because of widespread treatment with the cytotoxic anti-HIV drug AZT. 2) The distinctly low, 1.3-2%, annual AIDS risk of hemophiliacs, compared to the higher 5-6% annual risk of intravenous drug users and male homosexual aphrodisiac drug users--because transfusion of foreign proteins is less immunosuppressive than recreational drug use. 3) The age bias of hemophilia-AIDS, i.e. that the annual AIDS risk increased 2-fold for each 10-year increase in age--because immunosuppression is a function of the lifetime dose of foreign proteins received from transfusions. 4) The restriction of hemophilia-AIDS to immunodeficiency diseases--because foreign proteins cannot cause non-immunodeficiency AIDS diseases, like Kaposi's sarcoma. 5) The absence of AIDS diseases above their normal background in sexual partners of hemophiliacs--because transfusion-mediated immunotoxicity is not contagious. 6) The occurrence of immunodeficiency in HIV-free hemophiliacs--because foreign proteins, not HIV, suppress their immune system. 7) Stabilization, even regeneration, of immunity of HIV-positive hemophiliacs by long-term treatment with pure factor VIII. This shows that neither HIV nor factor VIII plus HIV are immunosuppressive by themselves. Therefore, AIDS cannot be prevented by elimination of HIV from the blood supply and cannot be rationally treated with genotoxic antiviral drugs, like AZT. Instead, hemophilia-AIDS can be prevented and has even been reverted by treatment with pure factor VIII.
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PMID:Foreign-protein-mediated immunodeficiency in hemophiliacs with and without HIV. 774 63

Human immunodeficiency virus (HIV), the retrovirus believed to be the cause of acquired immunodeficiency syndrome (AIDS), infects a variety of CD4+ cells, including lymphocytes and cells of the monocyte/macrophage lineage. Encoded in the HIV genome are several precursor proteins that must undergo proteolytic cleavage to yield functional proteins. The gag precursor protein of HIV (p55) is cleaved by a virally encoded aspartate protease (HIV protease). Because cleavage of p55 is required for viral maturation and infectivity, inhibition of HIV protease is an attractive target for therapy designed to block the progression of HIV infection. Inhibitors of HIV protease from a variety of chemical classes have been synthesized and antiviral activity has been demonstrated in lymphocytes and cells from the monocyte/macrophage lineage. A few HIV protease inhibitors have progressed to the clinic and some have shown promise in early trials. There are, however, several important issues that will affect the development of a successful HIV protease inhibitor, including cell and tissue distribution and immunotoxicity. These issues are tissue distribution and immunotoxicity. These issues are discussed, with an emphasis on the complexities posed by cells of the monocyte/macrophage lineage.
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PMID:HIV protease inhibitors: effects on viral maturation and physiologic function in macrophages. 808 11

Habitual abuse of nitrite inhalants has been linked in epidemiological studies with seropositivity to human immunodeficiency virus and, separately, with Kaposi's sarcoma among AIDS patients. Mice exposed to isobutyl nitrite in an inhalation chamber for 45 min/day for 14 days had depressed IgM and IgG antibody responses. The inhibition was dose-dependent at 750-900 ppm, but antibody responses were increased at an intermediate (600 ppm) dose. Gender differences in immunotoxicity were not observed. Antibody responses to a T-independent antigen (DNP-ficoll) were not affected by the immunotoxic exposure, suggesting that B-cells were refractory to the toxic exposure. Toxic exposure to isobutyl nitrite did not selectively deplete a particular spleen cell population, but caused equivalent reductions of T-cells and B-cells. Finally, exposed mice remained immunocompromised for 3-5 days after terminating exposures. Normal immune responses returned by 5-7 days, suggesting that inhibition of cellular function was reversible.
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PMID:Inhaled isobutyl nitrite compromises T-dependent, but not T-independent, antibody induction. 826 96

Saquinavir (Ro 31-8959; SQV) has been demonstrated to be a potent inhibitor of human immunodeficiency virus (HIV) proteinases and acts synergistically with dideoxynucleoside analogues. The aim of this study was to investigate the in vitro immunomodulatory effects of SQV on normal human peripheral blood mononuclear cells (PBMC) and on lamina propria mononuclear cells (LPMC). We used the drug either alone or in double and triple combination with AZT and ddC to assess whether SQV enhances the immunomodulatory effects induced by AZT and ddC that we previously observed. We demonstrated that SQV did not induce any modulation of the proliferative response either in PBMC or in LPMC. Similarly, NK cell-mediated cytotoxic activity and cytokine production were not modified by SQV. More importantly, SQV/AZT, SQV/ddC, and SQV/AZT/ddC combinations did not strengthen neither the inhibition of PBMC and LPMC proliferative response or the modulation of cytokine production induced by AZT, ddC, and AZT/ddC. On the other hand, the increased IL-2 production induced by AZT and ddC was not observed adding SQV to the dideoxynucleoside analogues. In conclusion, we demonstrated that SQV used in combination with AZT and ddC did not add any further immunotoxicity.
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PMID:Lack of immunotoxicity of saquinavir (Ro 31-8959) used alone or in double or triple combination with AZT and ddC. 979 27

Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy, but its effects on the immune system are relatively unknown. In this study we have investigated the in vitro effect of IDV on normal human peripheral blood mononuclear cells (PBMC). We used the drug alone or in double and triple combination with AZT and ddC to assess whether IDV interferes with the previously observed immunomodulatory effects induced by AZT and ddC. We found that proliferative response, induction of immunoglobulins (Ig) production and cytokine production was not modulated by IDV. More importantly, IDV used in double or triple combination with AZT and ddC, does not further strenghten the inhibition of proliferative response induced by AZT and is able to abrogate the inhibitory effect induced by ddC on proliferative response. Similarly, IDV/AZT, IDV/ddC and IDV/AZT/ddC combinations does not strenghten the modulation of TNF-alpha, IFN-gamma and IL-4 induced by AZT, ddC and AZT/ddC. On the other hand, IDV neutralizes the up-regulating effects of AZT on IL-2 production while the up-regulating effects of ddC on IL-2 production is not affected. These data suggest that IDV used in combination with AZT and ddC did not add any further immunotoxicity.
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PMID:Effect of indinavir used alone or in double or triple combination with AZT and ddC on human immune functions. 1498 53

Clinical tests are readily available for assessing severe loss of immune function in children with diseases such as AIDS or primary immunodeficiency. However tests that could reliably identify subtle immune changes, as might be expected to result from exposure to developmental immunotoxic agents, are not readily available. A number of tests are described which we believe have potential applicability for epidemiological studies involving developmental immunotoxicity. Several of the tests, such as T cell receptor rearrangement excision circles (TRECs) and cytokine measurements, while highly relevant from a biological standpoint, may be precluded from use at the current time, for either technical issues or insufficient validation. Immunophenotyping and measurement of serum immunoglobulin levels, on the other hand, are well validated. Yet they may require extraordinary care in experimental design and technical performance in order to obtain data that would consistently detect subtle changes, as these tests are not generally considered highly sensitive. Quantification of the immune response to childhood vaccine, while up to the present used sparingly, may represent an excellent indicator for developmental immunotoxicity when conducted under appropriate conditions.
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PMID:Biomarkers to assess potential developmental immunotoxicity in children. 1596 13

Drug therapy for human immunodeficiency virus (HIV) is highly effective in suppressing viral replication and restoring immune function in patients with HIV. However, this same treatment can also be associated with immunotoxicity. For example, zidovudine and various other antiretroviral agents are capable of causing bone marrow suppression. Agents used to treat opportunistic infections in these individuals, including ganciclovir, foscarnet, and sulfamethoxazole-trimethoprim, can cause additional hematotoxicity. Drug-drug interactions must also be considered and managed in order to control iatrogenic causes of immunotoxicity. In this review, we examine the normal immune response to HIV, and the benefits of antiretroviral therapy in prolonging immune function. We then discuss immune-related adverse effects of drugs used to treat HIV and the opportunistic infections that are common among these patients. Finally, we address in vitro, animal, and clinical evidence of toxicity associated with various combination use of these agents.
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PMID:Effects of antiretroviral therapy on immunity in patients infected with HIV. 1651 83

A number of regulatory agencies in western Europe, Japan and the United States now include guidelines for evaluating the potential immunotoxicity of chemicals, including drugs, as part of routine toxicity testing. Most testing guidelines recommend observational or functional assays that, based on studies in laboratory animals, are able to detect changes in immune function that are associated with increased susceptibility to infectious or neoplastic cell challenge. To appreciate how well observational and functional endpoints are likely to predict an increased risk of infection in humans, it is important to establish correlations between alterations in human immune function and an increased risk of disease. This review will address the clinical evidence for increased risk of disease in humans with mild to moderate levels of immunosuppression using examples from the literature, discuss specific immune system defects associated with increased rates of infection, and examine factors that impact the interpretation of clinical data. The most comprehensive data bases that address these relationships, those derived from patients with primary immunodeficiency and AIDS, are not discussed in this review. These are extreme examples of immunodeficiency and neither the specific clinical diseases that result, nor eventual outcomes, have much in common with that which occurs in individual with chronic mild-to-moderate immunosuppression.
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PMID:Suppression of immune function and susceptibility to infections in humans: association of immune function with clinical disease. 1895 37

Immunotoxicity can either be expressed as immunosuppression, or as allergy or autoimmunity. This paper deals with immunodeficiency investigation in the rat, and emphasis is given to the role of histopathology. As current guidelines for toxicity testing pay only marginal attention to the immune system, it is evident that improvements have been proposed for this type of study. For evaluating the immune system as a possible target, we chose a tiered testing approach, in which basis testing was done in a subacute toxicity study in the rat following the OECD guideline 407. General parameters of the immune system included careful histopathological evaluation of lymphoid organs and tissues combined with data on the weights of lymphoid organs, white blood cell parameters and serum immunoglobulin measurements. No parameters were included in this screening that would compromise these toxicity experiments (e.g. immunization). The outcome of this first tier determined the need for additional tier-two immune function studies that were aimed at confirming and characterizing further immunotoxicity, and that comprised non-specific and specific immune responses as well as host-resistance models to infectious diseases. The latter models are especially of great importance for human risk assessment. This tiered system has been validated by the known immunosuppressants azathioprine and cyclosporine A. Although conventional histopathology has shown its great value in identifying immunotoxic agents, morphological characterization can be improved by immunohistochemistry, hybrido-histochemistry (in situ hybridization) and morphometric analyses; these technologies are also important for the characterization of the mechanism of toxicant-induced immune alterations. Insight into the mechanism of action can also be provided by using specific animal models such as the athymic rat and the so-called severe combined immune deficient (scid) mouse, in which lymphoid cells of human and animal origin (e.g. thymus tissue) can be grafted. By comparing the sensitivity of the grafted tisues with immunotoxicants, data can be obtained that are useful for the assessment of the immunotoxicological risk for humans. Examples of chemicals that have been identified to be immunotoxic in the tiered test system in the rat are the environmental contaminants hexachlorobenzene and tributyltin oxide, and the results of these studies were discussed. Based on these data it was recommended that additional test parameters be incorporated into the existing OECD guideline.
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PMID:Developments of immunotoxicology methods in the rat and applications to the study of environmental pollutants. 2069 52


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