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Biomedical subjects

R G Titus

Publications and source records attributed to R G Titus.

At least 73 records · Page 4Linked to original sources
PubMed1990

The role of vector saliva in transmission of arthropod-borne disease.

Blood-sucking arthropod disease vectors all share one important feature: while probing for blood in the vertebrate host's skin they salivate into the wound they create. Recent studies on the pharmacological properties of vector saliva have revealed an array of activities that are potentially beneficial to both the vector and to the pathogen. These observations may help explain why certain vectors and pathogens have co-evolved. In this article, Richard Titus and Jose Ribeiro discuss the role vector saliva may play in disease transmission, and the prospects for its use in the control of arthropod-borne pathogens.

Journal Article↗
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↗
PubMed1988

Salivary gland lysates from the sand fly Lutzomyia longipalpis enhance Leishmania infectivity.

Leishmaniasis is a parasitic disease transmitted by phlebotomine sand flies. The role of sand fly saliva in transmission of the disease was investigated by injecting mice with Leishmania major parasites in the presence of homogenized salivary glands from Lutzomyia longipalpis. This procedure resulted in cutaneous lesions of Leishmania major that were routinely five to ten times as large and contained as much as 5000 times as many parasites as controls. With inocula consisting of low numbers of Leishmania major, parasites were detected at the site of injection only when the inoculum also contained salivary gland material. This enhancing effect of sand fly salivary glands on cutaneous leishmaniasis occurred with as little as 10 percent of the contents of one salivary gland of one fly. Material obtained from other bloodsucking arthropods could not mediate the phenomenon.

Animals↗
PubMed1987

Involvement of specific Lyt-2+ T cells in the immunological control of experimentally induced murine cutaneous leishmaniasis.

The involvement of Lyt-2+ T cells in the immunological control of cutaneous leishmaniasis was assessed by studying the course of the disease in mice in which the number of these cells was reduced by treatment with anti-Lyt-2 monoclonal antibody (mAb). Administration of anti-Lyt-2 mAb exacerbated Leishmania major-induced cutaneous lesions in both genetically resistant and susceptible mice. This effect correlated with a drastic reduction in the number of specific Lyt-2+ T cells generated during infection. These results, together with the observation that resistant mice possess higher numbers of specific Lyt-2+ T cells in lymph nodes draining their lesions than susceptible mice, 3 weeks after infection, indicate that Lyt-2+ T cells also play a role in the immunological control of Leishmania major-induced lesions.

Animals↗
PubMed1987

Variants with reduced virulence derived from Leishmania major after mutagen treatment.

After several in vitro treatments of a virulent population of Leishmania major with the mutagen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), five clones (vir-) were obtained that did not produce cutaneous lesions after subcutaneous injection of 10(6) promastigotes. All the control clones (vir+) obtained from the non-mutagenized parasite population produced progressive cutaneous lesions with as few as 10(3) parasites. Late lesions were observed occasionally after injection of 10(7) vir- parasites. These late lesions appeared to result from the selection of virulent revertants, since parasites isolated from these lesions produced progressive lesions in BALB/c mice almost as readily as the control parasites. Two vir- clones, one vir+ clone and one revertant clone were examined for survival in BALB/c macrophages in vitro. All clones were taken up by the macrophages and transformed into amastigotes. However, vir- clones failed to multiply inside the macrophages. A vir- clone was found to protect mice against a subsequent challenge with vir+ parasites.

Agglutination↗
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↗
PubMed1986

Inhibition and enhancement of in vitro helper activity of apocytochrome c-specific murine T cell populations and clones by anti-apocytochrome c-specific monoclonal antibodies.

A murine monoclonal antibody (mAb) specific for apocytochrome c was found to be able to either inhibit or enhance the helper activity of mouse apocytochrome c-specific T cell clones and populations in a hapten (trinitrophenyl)-carrier (apocytochrome c) system of T-B cell cooperation. This effect of the mAb was carrier specific, could not be ascribed simply to a shift in the kinetics of the antibody response and was observed using apocytochrome c T helper cells of different mouse haplotypes. In addition, the anti-apocytochrome c mAb was able to inhibit specific T helper cell activity even when the T cells were triggered with antigen-presenting cells pulsed with antigen. Taken together, these results suggested that the mAb was inhibiting helper activity due to its ability to modify the interaction between T cells and antigen-presenting cells.

Animals↗
PubMed1985

A limiting dilution assay for quantifying Leishmania major in tissues of infected mice.

A limiting dilution assay for the quantification of Leishmania major in infected mouse tissue was developed. The assay was found to be both sensitive and reliable, and, due to its design, could be scored either visually or following the incorporation of 3H-thymidine by the growing parasites. Results are presented in which the assay was employed to enumerate L. major in the tissues of susceptible (BALB/c) and resistant (CBA) mice at intervals after infection with L. major. It was found that parasites could be detected at the site of injection with L. major as early as 3 days after infection. By day 8, a substantial increase in the number of parasites at the lesion site had occurred in both strains of mice. Subsequently, whereas the number of parasites decreased in the lesions of CBA mice, their number steadily increased in the lesions of BALB/c mice. Parasites were detected in lymph nodes draining the lesion site in both BALB/c and CBA mice by 28 days after infection. Interestingly, a low number of L. major was found in the lymph nodes of CBA mice at 100 days after infection, a time when no parasites could be detected at the lesion site. Previous results from this laboratory have demonstrated that the adoptive transfer of L. major-specific L3T4-positive T-cell populations exacerbated cutaneous lesions induced by L. major in BALB/c mice. Experiments presented here indicate that the adoptive transfer of L. major-specific T-cells also exacerbated cutaneous leishmaniasis in CBA mice. Using the sensitive limiting dilution assay presently described, it was found that this unexpected exacerbative effect of L. major-specific T-cells on lesion development was accompanied by a substantial increase in the number of parasites in the lesions of the adoptively transferred mice.

Animals↗
PubMed1985

Therapeutic effect of anti-L3T4 monoclonal antibody GK1.5 on cutaneous leishmaniasis in genetically-susceptible BALB/c mice.

The effect of in vivo treatment with anti-L3T4 monoclonal antibody (mAb) on the course of experimentally-induced cutaneous leishmaniasis was studied in genetically susceptible BALB/c mice. Administration of anti-L3T4 mAb resulted in a pronounced therapeutic effect as reflected by both resolution of lesions and a dramatic reduction in the parasite load in treated mice. This effect was specific for anti-L3T4 mAb and correlated with a selective depletion of L3T4+ T cells in the lymphoid tissues of treated mice. Moreover, both the therapeutic effect of anti-L3T4 mAb on cutaneous leishmaniasis and the concurrent depletion of L3T4+ T cells in the lymphoid tissues of treated mice were dependent upon the isotype of the anti-L3T4 mAb employed.

Animals↗
PubMed1984

Intracellular destruction of Leishmania tropica by macrophages activated with macrophage activating factor/interferon.

Supernatants (SN) from cloned T cell lines, lymphokine secreting tumour cell lines and mixed lymphocyte culture were analysed for their ability to induce murine peritoneal exudate cell (PEC) macrophages (M phi) parasitized with Leishmania tropica to destroy the parasite. The ability of the SN to induce parasite destruction in parasitized PEC M phi correlated with their content of macrophage activating factor/interferon. Neither granulocyte-macrophage colony stimulating factor, M phi colony stimulating factor nor interleukin 2 was required for the induction of parasiticidal activity by infected PEC M phi. Similar results were also obtained using either a different Leishmania species, Leishmania enriettii, or a second source of cells: bone marrow derived macrophages.

Animals↗
PubMed1984

Exacerbation of murine cutaneous leishmaniasis by adoptive transfer of parasite-specific helper T cell populations capable of mediating Leishmania major-specific delayed-type hypersensitivity.

The effect of adoptive transfer of in vitro-propagated Leishmania major-specific T cell populations on the course of experimentally induced cutaneous leishmaniasis was studied in mice. The L. major-specific T cells expressed the T helper/inducer phenotype and were able in vitro to a) mount a specific proliferative response, b) provide specific helper activity for antibody responses, c) activate parasitized macrophages resulting in L. major destruction, and d) secrete macrophage-activating factors as tested in a tumoricidal assay. These T cells were also found capable of transferring parasite-specific delayed-type hypersensitivity responses to normal syngeneic mice. Results indicated that the i.v. transfer of these L. major-specific T cell populations into normal syngeneic mice exacerbated cutaneous lesions induced by infection with L. major. This effect on the disease process appeared to be dependent upon recognition of parasite antigens by the injected T cells because no exacerbation of the disease process was seen after the transfer of similar T cell populations specific for an antigen unrelated to the parasite, namely ovalbumin. However, the inclusion of ovalbumin in the L. major infecting inoculum resulted in an exacerbating effect of ovalbumin-specific T cells on cutaneous leishmaniasis. These unexpected results were supported by observations showing that immunization of mice with L. major antigens in complete Freund's adjuvant 7 days before infection with L. major led to exacerbated lesions. A similar aggravation of L. major-induced cutaneous lesions was also observed in mice previously immunized with an unrelated antigen provided that this antigen was included in the L. major infecting inoculum.

Animals↗
PubMed1981

A simple and effective method to assess murine delayed type hypersensitivity to proteins.

Mice sensitized with various protein antigens emulsified in complete Freund's adjuvant by a subcutaneous injection at the base of the tail exhibited both immediate and delayed type hypersensitivities 7-8 days following sensitization. Hypersensitivity was assessed by the degree of footpad swelling elicited by challenge with a heat-aggregated form of the antigen. The swelling response was specific for the antigen used for sensitization and often resulted in a near doubling of footpad thickness. Histological examination is conjunction with studies having passive transfer of serum and adoptive transfer of either T cell-enriched or T cell-depleted preparations indicated that whereas the immediate swelling response was achieved with serum, the delayed swelling response was mediated by T lymphocytes. Adoptive transfer of specific delayed type hypersensitivity was also accomplished with small numbers of lymph node T cells obtained following in vitro enrichment and propagation.

Animals↗
PubMed1981

Orally induced tolerance. Definition at the cellular level.

Several elements of the phenomenon of oral tolerance were examined. It was shown that whereas intragastric (i.g.) exposure of mice to the T-dependent antigens ovalbumin (OVA), bovine serum albumin, and human gamma globulin severely compromised the ability to respond to a subsequent challenge with the homologous antigen, i.g. treatment with T-independent antigens such as dinitrophenylated Ficoll, polyvinylpyrrolidone and bacterial lipopolysaccharide (LPS) did not induce anergy. Furthermore, mice parenterally primed to OVA were not only refractory to the induction of oral tolerance with OVA, but displayed an anamnestic response following i.g. treatment with the antigen. In a final line of investigation, it was shown that whereas mice administered OVA orally lost specific T cell functions such as the ability to (a) provide helper activity; (b) proliferate in response to antigen, and (c) mediate delayed-type hypersensitivity, such animals possessed OVA-specific functional B cells as evidenced by the ability to respond to OVA when the antigen was administered either linked to a recognizable carrier or in conjunction with LPS.

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↗