Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009450 (infectious diseases)
 83,438 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a pilot study the safety and therapeutic effects of an immunostimulatory intralymphatic treatment with natural human interleukin-2 (IL-2) in combination with zidovudine were evaluated in nine patients with AIDS. Therapy with IL-2 consisted of one subcutaneous injection of 0.1 microgram/kg IL-2, followed by four intralymphatic IL-2 infusions of 0.1 microgram/kg each within a period of up to 15 days. Enlargement of lymph nodes was seen in six and a transient increase of CD4 cells in five out of nine persons in association with the IL-2 therapy. An increase of HIV p24-antigenemia was observed only in the two patients in whom zidovudine dosage had to be reduced because of side effects. Moderate clinical side effects occurred in eight of the nine patients. Four patients developed zidovudine associated anemia. Six participants showed a favourable course of disease with survival of 25 to 54 months (median 30 months) despite a previous diagnosis of manifest AIDS before IL-2 therapy. This pilot study demonstrates that a combination therapy with intralymphatic IL-2 and zidovudine can induce positive immunomodulatory effects, even in the presence of manifest AIDS. Further studies should explore the tolerability and effects of a prolonged therapy with IL-2 in combination with a more potent antiviral drug combination therapy.
Infection
PMID:Intralymphatic interleukin-2 in combination with zidovudine for the therapy of patients with AIDS. 986 62

T cells are central players in the immune response to infectious disease, with the specificity of their responses controlled by the T-cell receptor (TCR)/CD3 complex on the cell surface. Impairment of TCR/CD3-directed CD4(+) T-cell immune responses is frequently observed in individuals infected with human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Virus replication is also regulated by T-cell activation factors, with HIV-1 and HIV-2 responding to different TCR/CD3-directed cellular pathways. We previously demonstrated that HIV-1 infection of the human interleukin-2-dependent CD4(+) T-cell line WE17/10 abrogates TCR/CD3 function and surface expression by a specific loss of CD3-gamma gene transcripts. In this study, we show that HIV-2 provokes the same molecular defect in CD3-gamma gene transcripts, resulting in a similar but delayed progressive loss of TCR/CD3 surface expression after infection.
 ...
PMID:Human immunodeficiency virus type 2 produces a defect in CD3-gamma gene transcripts similar to that observed for human immunodeficiency virus type 1. 1023 90

In some parasitic infections immunosuppression is a prominent characteristic of the host-parasite interplay. We have used a murine alveolar echinococcosis (AE) model in susceptible C57BL/6 mice to document a suppressed splenocyte proliferative response to concanavalin A (Con A) at the early (1-month) stage and to Echinococcus multilocularis-crude antigen (Emc-antigen) at the late (4-6-month) stage of chronic infection. Despite proliferative suppression, splenic cytokine production [interleukin-2 (IL-2), IL-4 and interferon-gamma (IFN-gamma)] in response to Con A or Emc-antigen stimulation was not suppressed at 1 month postinfection (p.i.). Infection resulted in a strong Mac-1+ cell infiltration of the peritoneal cavity and spleen. Peritoneal cells (PEC) from mice infected at the 1-month stage were rich in macrophages and expressed significantly higher levels of transcripts for the inflammatory cytokine IL-1beta and for tumour necrosis factor-alpha and inducible nitric oxide synthase (iNOS), when compared with PEC from non-infected control mice. Conversely, the IL-10 transcript level remained low and did not change during infection. Spleen cells supplemented with PEC from infected mice induced a marked increase in the levels of nitrite in response to Con A and Emc-antigen stimulation, and also a complete suppression of splenic proliferation. The spleen cells from late-stage infected mice expressed only background levels of IL-10 but greatly increased levels of iNOS, when compared with normal spleen cells. This observation correlated with the immunosuppression demonstrated at the late stage of murine AE. Furthermore, the suppressed splenic proliferative responses observed at the early and late stage were reversed to a large extent by the addition of NG-monomethyl-l-arginine and partially by anti-IFN-gamma. Thus, our results demonstrated that the immunosuppression observed in chronic AE was not primarily dependent on IL-10 but rather on nitric oxide production by macrophages from infected animals.
 ...
PMID:Nitric oxide-mediated immunosuppression following murine Echinococcus multilocularis infection. 1044 21

As we move into the next century it appears that new antituberculosis drugs will arise from four categories: 1) new use of old drugs, 2) new delivery of old drugs, 3) new drugs within old classes, and 4) new classes of drugs. Old drugs such as clofazimine and its analogues, rifabutin, the macrolides, aminoglycosides, quinolones and perhaps vitamin D may find a way into better regimens. New therapy may also arise from new combinations and new uses of current antituberculosis drugs. New drugs are being developed in the rifamycin, fluoroquinolone, and nitroimidazole families. Several immune amplifiers, such as interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and interleukin-12 (IL-12) have undergone pilot testing. Counteracting adhesion molecules is being tested for several infectious diseases. With the unraveling of the tuberculosis genome, attacking enzymes unique to Mycobacterium tuberculosis is easier and allows us to hit elements in both a metabolic pathway and its alternate pathway. Interfering with transcription factors that bind DNA but do not promote RNA production could interrupt transcription. Genetic products of mycobacteria can be modified to cause their own death. Phages may deliver antisense nucleic acids for inhibition of mycobacterial gene expression. The distinction between drugs, immunotherapies and vaccines may blur.
 ...
PMID:Tuberculosis treatment for the beginning of the next century. 1046 97

A decrease in lymphocyte signal-transduction molecules, described in cancer patients and patients with chronic infectious diseases, has been proposed as a possible mechanism leading to an impaired immune response in cancer patients. Here we report the effects of combination immunotherapy on the levels of T cell receptor zeta chain and p56lck tyrosine kinase in a retrospective study of cryopreserved lymphocytes from 26 metastatic renal cell carcinoma patients treated with high-dose interleukin-2 (IL-2), interferon alpha (IFNalpha) and ex vivo IL-2-activated lymphocytes. Of the 26 patients, 12 were responders (5 complete and 7 partial) and 14 were non-responders (6 stable and 8 with progressive disease). Prior to treatment, 21 of 26 patients (81%) and 13 of 21 patients (62%) respectively expressed zeta chain and p56lck at less than 50% of the levels observed in healthy controls. During therapy, this low zeta chain and p56lck expression increased to at least 50% of normal in 13 of the 21 patients (62%) and in 6 of the 13 patients (46%) respectively; in the remaining patients expression levels remained at 50% of normal or more, or declined. Although, in this limited study, pretreatment levels of and p56lck did not show significant correlation with antitumor response, 4 of 5 patients that achieved a complete response (80%) corrected both zeta chain and p56lck levels to at least 50% of normal, while restoration of both signal-transduction molecules to such levels was only observed in 3 of 7 partial responders (43%), 1 of 5 patients with stable disease (20%) and 2 of 7 patients with progressive disease (29%). Thus, these results suggest that analysis of changes in signal-transduction molecules may a be useful tool for immunological monitoring of patients throughout immunotherapy, and could provide important information for designing new clinical trials that restore impaired signal transduction while activating T cell responses.
 ...
PMID:Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy. 1047 43

The cytokines interleukin-2 and interferon-alpha are potent biological agents used to treat malignancy, infectious diseases, and neurodegenerative disorders. While these medications show substantial therapeutic promise, the neuropsychiatric toxicity associated with these agents is often treatment-limiting. The pathophysiology of this toxicity is not well delineated, and adverse effects to the central nervous system are often misdiagnosed by clinicians. This report reviews the preclinical and clinical literature describing the morbidity associated with these agents and suggests appropriate clinical management strategies and future directions for research.
 ...
PMID:Neuropsychiatric toxicity associated with cytokine therapies. 1047 48

Occupancy of CTLA-4 (cytotoxic T-lymphocyte antigen-4 or CD152) negatively regulates the activation of mouse T lymphocytes, as indicated by the fate of CTLA-4-deficient mice, by the impact of anti-CTLA-4 monoclonal antibodies (mAbs) on mouse T-cell activation in vitro and by the impact of CTLA-4 blockade on the course of experimental tumoral, autoimmune, alloimmune or infectious disease in this animal. The function of human CTLA-4, however, remains less clear. The expression and function of human CTLA-4 were further explored. CTLA-4 was expressed under mitogenic conditions only, its expression being, at least partially, dependent on the secretion of interleukin-2. Memory T cells expressed CTLA-4 with faster kinetics than naive T cells. The functional role of human CTLA-4 was assessed utilizing a panel of four anti-CTLA-4 mAbs that blocked the interaction between CTLA-4 and its ligands. These mAbs, in immobilized form, profoundly inhibited the activation of T cells by immobilized anti-CD3 mAb in the absence of anti-CD28 mAb, but co-stimulated T-cell activation in the presence of anti-CD28 mAb. Finally, and importantly, blockade of the interaction of CTLA-4 with its ligands using soluble anti-CTLA-4 mAbs, in intact form or as Fab fragments, enhanced T-cell activation in several polyclonal or alloantigen-specific CD80- or CD80/CD86-dependent assays, as measured by cytokine production, cellular proliferation or cytotoxic responses. It is concluded that interaction of CTLA-4 with its functional ligands, CD80 or CD86, can down-regulate human T-cell responses, probably by intracellular signalling events and independent of CD28 occupancy.
 ...
PMID:Interaction of CTLA-4 (CD152) with CD80 or CD86 inhibits human T-cell activation. 1058 2

Infection-associated immunoincompetence during malaria might result from macrophage dysfunction. In the present study, we investigated the role of macrophages as target for immunosuppression during infection, using the murine Plasmodium c. chabaudi model. Special attention has been paid to the analysis of processing/presentation of protein antigens and presentation of peptides, using cocultures of peritoneal exudate cells (PECs) from infected mice and antigen-specific T-cell hybridomas. The results obtained indicate a defective processing of protein antigens that becomes maximal at acute parasitemias. In addition, macrophages from acutely infected mice suppress the interleukin-2 production by the antigen-activated T-cell hybridomas. This effect was independent of prostaglandin and nitric oxide production by the macrophage. The possible role of parasite components in the impaired accessory cell function of PECs was investigated and hemozoin, the end-product of the hemoglobin catabolism by intraerythrocytic malaria parasites, was found to induce similar infection-associated deficiencies in vitro. Moreover, hemozoin, was shown to mimic the immunosuppressive effects induced in PECs during in-vivo infections with P. chabaudi. In conclusion, we propose that hemozoin is a key factor in the malaria-associated immunosuppression, affecting both the antigen processing and immunomodulatory functions of macrophages.
 ...
PMID:Hemozoin is a key factor in the induction of malaria-associated immunosuppression. 1058 55

We have previously demonstrated that Epstein-Barr virus (EBV) strain B95.8 can infect and initiate a partial transcriptional program in both CD4+ and CD8+ lymphocytes (Guan, M. X., R.-D. Zhang, B. Wu, and E. E. Henderson. 1996. J. Virol. 70:7341-7346). Experiments were undertaken to determine whether EBV infection can alter the growth potential of T lymphocytes. Peripheral blood lymphocytes were separated into populations consisting of 99.8% CD4+ and 98.6% CD8+ T lymphocytes by FACS. Infection of these populations with EBV resulted in blastogenesis in both CD4+ and CD8+ populations. Clones were established from the CD4+ population in the presence of interleukin-2. Two of these clones expressed the T cell surface markers CD3 and CD4 and carried the EBV genome. One lymphoblastoid cell line (LCL) had a mixture of CD4+ and CD19+ cells. The T-LCLs harboring the EBV genome in circular form and transcribed mRNA transcripts corresponding to BZLF1, BRLF1, BMLF1, and EBER-1 and -2. Immunofluorescence demonstrated EBNA in the nucleus of T rosette-positive lymphoblasts with an absence of viral capsid antigen expression. In situ hybridization for EBER showed nuclear and cytoplasmic staining in B95.8 cells, whereas EBV-carrying T-LCLs only showed nuclear staining. These results demonstrate that EBV can both infect and induce growth transformation of T lymphocytes, supporting a direct role for EBV in AIDS-related, EBV-associated T cell lymphomas. A better understanding of the EBV transcriptional program during EBV-induced T cell transformation could directly lead to adoptive T cell therapeutic strategies and/or more effective antiviral chemotherapy for EBV-associated T cell lymphoma.
 ...
PMID:Epstein-Barr virus (EBV)-induced long-term proliferation of CD4+ lymphocytes leading to T lymphoblastoid cell lines carrying EBV. 1065 85

CCR5 and CXCR4 are the major coreceptors that mediate human immunodeficiency virus 1 (HIV-1) infection, while most simian immunodeficiency virus (SIV) isolates use CCR5. A number of alternative coreceptors can also mediate infection of some virus strains in vitro, although little is known about their in vivo relevance. Therefore, we characterized the expression pattern and coreceptor activity of one of these alternative coreceptors, STRL33/Bonzo, using a newly developed monoclonal antibody. In addition to being highly expressed (approximately 1000-7000 STRL33 ABS [antibody binding sites]) on specific subsets of natural killer cells (CD3(-)/CD16(-/low)/CD56(+) and CD3(-)/CD16(low)/CD56(-)) and CD19(+) B lymphocytes (approximately 300-5000 STRL33 ABS), STRL33 was expressed at levels sufficient to support virus infection on freshly isolated, truly naive CD4(+)/CD45RA(+)/CD62L(+) cells (6000-11 000 ABS). STRL33 expression on peripheral blood mononuclear cells (PBMCs) was increased by mitogenic stimulation (OKT3/IL-2 [interleukin-2] had a greater effect than phytohemaglutinin (PHA)/IL-2), but it was dramatically decreased upon Ficoll purification. Infection of CCR5(-) human peripheral blood lymphocytes (PBLs) showed that 2 different SIV envelope (Env) proteins mediated entry into STRL33(+) cells. More importantly, the preferential infection of STRL33(+) cells in CCR5(-) PBLs by an R5/X4/STRL33 HIV-1 maternal isolate in the presence of a potent CXCR4 antagonist (AMD3100) suggests that STRL33 can be used as a coreceptor by HIV-1 on primary cells. Rhesus macaque (rh) STRL33 was used less efficiently than human STRL33 by the majority of SIV Env proteins tested despite similar levels of expression, thereby making it less likely that STRL33 is a relevant coreceptor in the rhesus macaque system. In summary, the expression pattern and coreceptor activity of STRL33 suggest its involvement in trafficking of tumor-infiltrating lymphocytes and indicate that STRL33 may be a relevant coreceptor in vivo.
 ...
PMID:Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. 1089 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>