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R G Titus

Publications and source records attributed to R G Titus.

15 recordsLinked to original sources
PubMed1992

Transcription of the tumor necrosis factor alpha gene is rapidly induced by anti-immunoglobulin and blocked by cyclosporin A and FK506 in human B cells.

The human tumor necrosis factor alpha (TNF-alpha) gene encodes a cytokine whose activities have been implicated in many immunopathological processes, including the activation and differentiation of lymphocytes. Originally identified as a monocyte factor, our studies and those of others have demonstrated that B and T lymphocytes produce TNF-alpha when stimulated by a variety of inducers. We report here that TNF-alpha gene transcription is rapidly and highly induced in three independently derived human Burkitt lymphoma cell lines, as well as in freshly isolated human splenic B cells, activated by antibodies to surface immunoglobulin. This burst in TNF-alpha gene transcription is associated with an induction of TNF-alpha bioactivity in the culture supernatants from stimulated splenic B cells. Moreover, induction of TNF-alpha gene transcription by anti-immunoglobulin was blocked by the immunosuppressants cyclosporin A and FK506. These studies demonstrate that TNF-alpha production is an early event in B-cell activation and they establish the efficacy of using immunosuppressants as probes in dissecting transcriptional activation pathways in human B cells.

B-Lymphocytes↗
PubMed1992

Recombinant human migration inhibitory factor has adjuvant activity.

Recombinant human migration inhibitory factor (MIF), isolated through functional expression cloning in COS-1 cells, up-regulates expression of genes encoding HLA-DR and interleukin 1 beta (IL-1 beta) and elaboration of IL-1 beta by human monocyte-derived macrophages. Administration of soluble bovine serum albumin or human immunodeficiency virus 120-kDa glycoprotein (HIV gp120) to mice in the presence of recombinant MIF together with incomplete Freund's adjuvant induced a strong T-cell proliferative response comparable to that of complete Freund's adjuvant. Recombinant MIF also increased antibody production, especially of IgG1 and IgM, in mice. Taken together, these results indicate that recombinant MIF may be useful as an adjuvant in the development of vaccines.

Adjuvants, Immunologic↗
PubMed1991

Colchicine is a potent adjuvant for eliciting T cell responses.

The cytotoxic drug colchicine when administered to mice in conjunction with Ag was shown to have a strong adjuvant effect in generating a specific plaque-forming cell response to the protein Ag OVA, human gamma-globulin and BSA. Dissection of this phenomenon revealed that several T cell activities, including Th function, Ag-induced T cell proliferation and T cell-mediated delayed-type hypersensitivity, were also specifically induced by treating mice with colchicine + Ag. The adjuvant effect of colchicine was observed when the drug and Ag were injected in soluble form, i.e., no vehicle (e.g., oil, liposome) was necessary. The potency of colchicine as an adjuvant was equal to or more than that of conventional adjuvants such as CFA or alum.

Adjuvants, Immunologic↗
PubMed1991

Exacerbation of experimental murine cutaneous leishmaniasis with CD4+ Leishmania major-specific T cell lines or clones which secrete interferon-gamma and mediate parasite-specific delayed-type hypersensitivity.

Leishmania major-specific T cell lines were derived from mice sensitized to the parasite. The cells were of the CD4+ T cell lineage and, upon adoptive transfer, were found to be capable of inducing parasite-specific delayed-type hypersensitivity. Adoptive transfer of these L. major-specific T cells to syngeneic recipients which were either normal, T cell deficient or B cell and antibody deficient led to exacerbation of infection upon subsequent challenge with L. major. This suggested that host T cells, B cells and antibody were not required for the L. major-specific T cells to exert their exacerbative effect on the course of cutaneous leishmaniasis. Additional studies revealed that the adoptive transfer of graded doses of these L. major-specific T cells always resulted in exacerbation of infection. Study of the localization pattern of the cells following transfer showed that they migrate preferentially to the site of the lesions. Furthermore, although the induction phase of this phenomenon was immunologically specific, its effector phase was not. Finally, T cell clones were derived from the L. major-specific T cell lines. The T cell clones were phenotypically and functionally identical to the T cell lines from which they were derived. Adoptive transfer of these parasite-specific T cell clones to normal syngeneic recipients induced an exacerbated course of infection with L. major. Interestingly, when these cloned T cells were specifically activated in vitro, the cells produced interleukin 2 and interferon-gamma, but no interleukin 4, indicating that they belong to the murine Th1 subset of CD4+ T cells.

Animals↗
PubMed1991

The involvement of TNF, IL-1 and IL-6 in the immune response to protozoan parasites.

One early reaction of the host to infection with protozoan parasites is the secretion of an array of potent cytokines including tumor necrosis factor (TNF), interleukin (IL-1) and IL-6. The combined action of these cytokines causes fever, leukocytosis and the production of acute phase proteins such as C-reactive protein (CRP). These early responses contribute significantly to the outcome of infection by influencing the course of infection directly and by regulating the specific immune response to the parasite.

Acute-Phase Proteins↗
PubMed1991

Analysis of enhancing effect of sand fly saliva on Leishmania infection in mice.

Salivary gland lysates of the sand fly Lutzomyia longipalpis markedly enhance the course of infection with Leishmania major in mice. Here we examine various parameters of this phenomenon. The exacerbative effect of L. longipalpis salivary gland lysates occurred in five different mouse strains; however, the character of the effect varied from one strain to another. Consistent exacerbation of infection was achieved with as little as 1/10 of a gland. The exacerbative effect applied to more than one Leishmania species and to more than one species of sand fly, since salivary gland lysates of L. longipalpis enhanced infection with L. mexicana amazonensis and salivary gland lysates of Phlebotomus papatasi enhanced infection with L. major. A synthetic rat calcitonin gene-related peptide was also found to exacerbate infection with L. major but was found to be approximately 100-fold less potent than saliva in mediating this effect. In addition, lesions induced at skin sites at which L. longipalpis had probed for a blood meal exhibited an exacerbated course of infection similar to that seen when parasites were injected with sand fly salivary gland lysates.

Animals↗
PubMed1991

Role of tumor necrosis factor in macrophage leishmanicidal activity in vitro and resistance to cutaneous leishmaniasis in vivo.

Recombinant human tumor necrosis factor (TNF) and purified murine TNF were both able to activate macrophages to destroy intracellular Leishmania major in vitro. In addition, parasitizing macrophages with L. major markedly increased the ability of the cells to produce TNF. Finally, when mice were vaccinated with an avirulent form of L. major, the animals produced large amounts of TNF but no gamma interferon in response to infection with virulent L. major. Treating these mice with a neutralizing anti-TNF antibody led to partial but not complete inhibition of the resistant state, which suggests that factors other than TNF and gamma interferon contribute to resistance to L. major.

Animals↗
PubMed1990

Leishmania major: nature of immunity induced by immunization with a mutagenized avirulent clone of the parasite in mice.

A chemically mutagenized avirulent form of Leishmania major was used to immunize BALB/c and C57B1/6 mice against challenge with virulent L. major. Immunity was elicited when the avirulent parasite was injected intravenously or intraperitoneally, but not subcutaneously. In fact, the latter route of immunization sometimes resulted in exacerbation of a subsequent infection with virulent L. major. Mice immunized with avirulent L. major developed upon challenge with virulent L. major cutaneous lesions which were significantly smaller and contained substantially fewer parasites than lesions on control nonimmune animals. Finally, the protection conferred by immunization with avirulent L. major could be adoptively transferred with T cells of the CD4+ lineage but not the CD8+ lineage.

Animals↗
PubMed1990

Patterns of cytokine secretion in murine leishmaniasis: correlation with disease progression or resolution.

Susceptibility or resistance to infection with Leishmania major correlates with the ability of mice to produce characteristic panels of lymphokines in response to the parasite. To investigate the role of antigen-presenting cells in this phenomenon, we developed a model system which used congenic (H-2d) susceptible and resistant mice. L. major-specific T cells were isolated from infected BALB/c and B10.D2 mice, and the cells were restimulated in vitro on syngenic or congenic antigen-presenting cells. BALB/c L. major-reactive T cells restimulated with either antigen-presenting cell produced high levels of interleukin-4 and low levels of gamma interferon. In contrast, T cells from B10.D2 mice produced gamma interferon. Radiation-induced chimeras reconstituted with BALB/c bone marrow also produced more interleukin-4 in response to L. major than did chimeras reconstituted with B10.D2 bone marrow. To test whether this pattern of cytokine secretion was unique to infection with L. major, we infected the mice with a second intracellular pathogen, Mycobacterium bovis BCG. Mycobacterium-specific T cells from both BALB/c and B10.D2 mice produced interleukin-2 and no interleukin-4. Finally, when BALB/c mice were vaccinated with avirulent L. major, the induced resistance correlated with reduced production of interleukin-4 but no increase in gamma interferon production. Instead, T cells from the vaccinated mice produced high levels of tumor necrosis factor. This suggests that tumor necrosis factor, in addition to gamma interferon, may be involved in resistance to L. major and that interleukin-4 may inhibit the leishmanicidal activity of tumor necrosis factor and/or gamma interferon.

Animals↗
PubMed1989

Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis.

The ability of mice to resist infection with L. major correlated directly with the capacity of their LNC to produce TNF in response to in vitro parasite challenge. Blocking TNF in vivo by passively administering anti-TNF antibodies exacerbated the course of L. major infection, resulting in substantially larger cutaneous lesions and elevated numbers of parasites within those lesions. In addition, treatment of infected mice with exogenous rHuTNF afforded host protection as evidenced by smaller lesion size and decreased parasite counts. Taken together, these results suggest a central role for TNF in resistance to L. major.

Animals↗
PubMed1989

Peptides encoded by the calcitonin gene inhibit macrophage function.

Neuropeptides are considered to play an important role in the modulation of a number of immune functions. Calcitonin gene-related peptide (CGRP), one of the neuropeptides, was found to profoundly inhibit the ability of macrophages to produce H2O2 in response to IFN-gamma or to act as APC. For the inhibition of H2O2 production to occur, preincubation of the macrophages with CGRP was required. Among neuropeptides that are similar in size, calcitonin also prevented macrophage activation but adrenocorticotropic hormone did not. These findings suggest that CGRP and calcitonin play an important role in modulating the ability of macrophages to present Ag and to respond to activating factors.

Adrenocorticotropic Hormone↗
PubMed1986

Higher frequency of Leishmania major-specific L3T4+ T cells in susceptible BALB/c as compared with resistant CBA mice.

In previous studies, we reported that a) the adoptive transfer of parasite-specific L3T4+ T cells enhanced rather than inhibited the development of lesions induced by Leishmania major in normal BALB/c mice, and b) the depletion in vivo of L3T4+ T cells by administration of anti-L3T4 monoclonal antibody reversed the susceptibility of BALB/c mice to L. major. To further assess the role of specific L3T4+ T cells in the development of lesions induced by L. major in BALB/c mice, the frequency of parasite-specific T cells capable of mediating specific delayed-type hypersensitivity (DTH) reactivity was determined, by limiting dilution analysis, in the lymph nodes draining the lesions of susceptible (BALB/c) and resistant (CBA) mice. The numbers of L. major-specific DTH-mediating T cells was found to be substantially increased in the lymph nodes of infected BALB/c mice as compared with CBA mice. Moreover in CBA mice, analysis of the cell surface phenotype of the L. major-specific DTH-mediating T cells showed that these cells were equally represented in the L3T4+, Lyt-2-, and L3T4- Lyt-2+ subsets, whereas the majority of these cells in BALB/c mice expressed the L3T4+ Lyt-2- surface phenotype.

Animals↗
PubMed1979

Experimental syphilis in the rabbit: passive transfer of immunity with immunoglobulin G from immune serum.

A preparation of immunoglobulin G isolated from a pool of immune sera derived from rabbits with long-term syphilis was shown to possess a high degree of purity as judged by immunodiffusion and protein electrophoresis. The antitreponemal power of the preparation of immunoglobulin G and that of the immune serum pool from which it was derived were found to be equivalent in both the skin protection and the systemic protection test. The observation that neither normal serum nor a pool of serum derived from animals "immunized" with Salmonella typhi, Escherichia coli, Streptococcus pyogenes, or zymosan was protective indicates that the protective power of the immune serum studied was due to specific antibodies residing principally, if not entirely, in the immunoglobulin G fraction of the serum.

Animals↗
PubMedDate not supplied

Synergy between activated Leishmania major-specific CD4+ T lymphocytes and bone-marrow-derived cells in the exacerbation of murine cutaneous leishmaniasis.

Mechanisms of exacerbation of murine cutaneous leishmaniasis mediated by Leishmania major-specific CD4+ T lymphocytes were studied. Using a limiting dilution assay for the quantification of Leishmania parasites, the infected tissues (footpad) of lethally irradiated mice were found to contain tenfold less parasites at four days of infection than the footpads of infected unirradiated animals. Injection of bone marrow cells depleted of T cells into irradiated mice at the site of infection led to an increase in parasite numbers to levels equivalent to those seen in unirradiated mice. After injection of either L. major-specific CD4+ T cells, previously shown to exacerbate cutaneous leishmaniasis, into the infected footpad or the intravenous (i.v.) injection of bone marrow cells depleted of T cells, the numbers of parasites in lesions of irradiated mice never reached the values found in unirradiated control mice. In contrast, the concomitant transfer of CD4+ T-cell populations in situ and bone marrow cells depleted of T cells intravenously led to an increase in parasite loads in irradiated mice up to levels comparable to those of the unirradiated mice. This suggested that recruitment of myelomonocytic cells at the site of the lesions plays a role in the exacerbation of murine cutaneous leishmaniasis mediated by these CD4+ T lymphocytes. Finally, a similar effect was observed with T cells specific for an antigen unrelated to Leishmania, provided that this antigen was added to the L. major infecting inoculum.

Animals↗