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Biomedical subjects

M S Meltzer

Publications and source records attributed to M S Meltzer.

At least 91 records · Page 5Linked to original sources
PubMed1987

The symmetry of hip bone mineral density. A dual photon absorptiometry approach.

Dual photon absorptiometry studies were performed on the hips of 23 patients to determine whether bone mineral density values obtained from one hip were indicative of the values in the contralateral hip of the ambulatory patient. The femoral neck, trochanteric, and Ward's triangle areas of both hips were analyzed. There were no significant differences between the right and left hip bone mineral density measurements in any of these three areas. Since the right and left hip readings were highly correlated, either hip may be used to evaluate osseous status.

Adult↗
PubMed1987

Mycobacterium bovis BCG-induced protection against cutaneous and systemic Leishmania major infections of mice.

We examined the protective effects of Mycobacterium bovis bacillus Calmette-Guérin (BCG) administration on Leishmania major infections of BALB/c and P/J mice. There were two treatment protocols. In the first, the footpads of naive animals were inoculated with mixtures of L. major and BCG (viable or heat killed) or the soluble mycobacterial antigen, purified protein derivative. Viable BCG, but not heat-killed BCG or purified protein derivative, inoculated with L. major amastigotes into the footpads of naive BALB/c or P/J mice protected these animals from the metastatic spread of parasites to the viscera and from ensuing lethal systemic infection. This treatment also induced cures of the cutaneous lesions of P/J mice but not of BALB/c mice. In the second protocol, we induced an immune response to BCG before inoculation of L. major. BCG given intraperitoneally 10 days before infection of footpads with leishmania offered protection against the metastatic spread of amastigotes in both P/J and BALB/c mice, regardless of intralesional treatment, and modulated the severity of cutaneous infection by 30 to 50%. Inoculation of a mixture of viable BCG and L. major amastigotes into BCG-immune mice completely protected both BALB/c and P/J strains from cutaneous disease; we recovered no parasites from the inoculated footpads of these animals. Furthermore, each of the nonspecifically protected mice of both the BALB/c and P/J strains developed immunity to rechallenge with viable L. major. Injection of amastigotes at a site remote from the original lesion, the contralateral footpad, resulted in the complete clearance of parasites in the inoculum with no evidence of either cutaneous or systemic disease over an extended observation period.

Adjuvants, Immunologic↗
PubMed1986

Inhibition of lymphokine-induced macrophage microbicidal activity against Leishmania major by liposomes: characterization of the physicochemical requirements for liposome inhibition.

Resident peritoneal macrophages from untreated mice develop potent microbicidal activity against amastigotes of Leishmania major after in vitro treatment with lymphokine (LK) from mitogen-stimulated spleen cells. LK-induced macrophage microbicidal activity was completely and selectively abrogated by treatment with phosphatidylcholine-phosphatidylserine (PC/PS) liposomes. Other macrophage effector functions (phagocytosis, tumoricidal activity) were unaffected, as was cytotoxicity by macrophages activated in vivo or by LK in vitro before liposome treatment. Activation factors in LK were not adsorbed or destroyed by liposomes. Liposome-induced inhibition was unaffected by indomethacin and was fully reversible: macrophages washed free of liposomes developed strong microbicidal activity with subsequent LK treatment. Changes in liposomal lipid composition markedly altered suppressive effects, but inhibition was not dependent on liposome size, cholesterol content, charge, or number of lamellae. Liposomes composed of PC alone or in combination with any of five different phospholipids were not suppressive. In contrast, inhibition was directly dependent on PS concentration within PC/PS liposomes. Phosphoserine was not inhibitory nor was dimyristoyl PS (synthetic saturated PS). However, the lysophospholipid metabolite of PS, lysoPS, was strongly suppressive. These studies suggest that the reversible and selective inhibition of LK-induced macrophage microbicidal activity by PC/PS liposomes is mediated by PS and its lysoPS metabolite.

Animals↗
PubMed1986

A lymphokine distinct from interferon-gamma that activates human monocytes to kill Leishmania donovani in vitro.

Human interferon-gamma (IFN-gamma), a T cell lymphokine (LK), activates monocytes to kill many intra- and extracellular pathogens. In fact, previous reports assert that all activity in LK for macrophage activation is due to IFN-gamma. To test this assertion, we examined monocyte interactions with amastigotes of Leishmania donovani after treatment with recombinant DNA or affinity-purified leukocyte IFN-gamma and IFN-gamma containing LK. Cells treated with at least 200 IU/ml IFN-gamma were microbicidal for L. donovani. Analysis of IFN-gamma dose responses for induction of microbicidal activity by recombinant IFN-gamma (r-IFN-gamma) and LK, however, documented a striking difference: LK was 25-fold more efficient than r-IFN-gamma at equivalent IFN-gamma titers. This large difference suggested that monocyte activation factor(s) in LK may not be IFN-gamma. Rabbit anti-IFN-gamma completely inhibited antiviral activity in LK but did not abrogate the ability to induce monocyte cytotoxicity against leishmania. Furthermore, removal of IFN-gamma from LK by monoclonal anti-IFN-gamma affinity chromatography or by treatment with anti-IFN-gamma followed by staphylococcal protein A chromatography also did not inhibit LK activity. Fractionation of LK on Sephadex G-100 revealed two activity peaks: one in the 50,000 to 60,000 m.w. range coincident with IFN-gamma, and the other at 25,000 to 30,000 daltons with no IFN-gamma. These studies document LK physicochemically and antigenically distinct from IFN-gamma that activate monocytes to kill L. donovani. Such novel factors may have broad import for the study of macrophage-mediated host defenses and for development of immunotherapeutic regimens.

Animals↗
PubMed1985

Human monocyte activation for cytotoxicity against intracellular Leishmania donovani amastigotes: induction of microbicidal activity by interferon-gamma.

Macrophages are pivotal cells in interactions of man and leishmania. Leishmanial disease results from intracellular infection of macrophages: parasitized cells are seen in smears or biopsy specimens of lesions; macrophages cultured in vitro support replication of parasites. Paradoxically, parasite destruction is also mediated by macrophages, which become highly cytotoxic after exposure to immune lymphocytes or their lymphokine (LK) products. The precise molecular mechanisms by which lymphocytes or LK induce macrophage activation for leishmanicidal activity, however, are not yet known. We analyzed interactions of leishmania amastigotes with human monocytes cultured in vitro as a nonadherent cell pellet. Leishmania donovani and L. major replicated in freshly isolated monocytes. Monocytes treated with greater than 200 IU/ml of the LK, human Interferon-gamma (IFN-gamma), destroyed tumor cells and L. donovani, but not L. major. Phorbol myristate acetate, endotoxic bacterial lipopolysaccharide, and recombinant human IFN-alpha and IFN-beta did not induce cytotoxicity. The time course for induction of cytotoxicity contrasted sharply with that of previously described monocyte antileishmanial activity: IFN-gamma induced cytotoxicity even when added after infection with L. donovani; induction of cytotoxicity did not require that IFN-gamma be present throughout the period of culture after infection: a 30-min preinfection pulse of IFN-gamma was sufficient to induce 70% of maximal activity; and freshly isolated monocytes and cells cultured for up to 4 days in vitro prior to infection and IFN-gamma treatment were equally responsive to IFN-gamma. These studies provide convincing evidence for intracellular cytotoxicity for L. donovani by freshly isolated human monocytes. This system provides an important base for further analysis of induction and expression of cytotoxic mechanisms against leishmania and other intracellular organisms that cause human disease.

Animals↗
PubMed1985

Lymph node involvement in leishmaniasis.

Two U.S. Army soldiers acquired skin lesions of cutaneous leishmaniasis and enlarged lymph nodes while stationed in Panama. In the first case, parasites were histologically identified and cultured from the skin lesion and a contralateral lymph node. In the second case, parasites were cultured from an enlarged lymph node in a nodal group draining the lesion. These findings suggest that metastasis of cutaneous leishmanial infection may be more common than is generally appreciated.

Adult↗
PubMed1985

A papular eruption associated with human T cell lymphotropic virus type III disease.

The clinical spectrum of human T cell lymphotropic virus type III (HTLV-III) disease is associated with myriad cutaneous findings, commonly of infectious origin. A clinically characteristic, yet histologically nonspecific, papular eruption was observed in seven of thirty-five patients followed up for HTLV-III disease (acquired immunodeficiency syndrome and the related complex). Noncoalescing 2- to 5-mm skin-colored papules of the head, neck, and upper trunk typify the lesions. Histologically, a chronic perivascular infiltrate of mononuclear cells was regularly present. The eruption was often, but not always, pruritic. The clinical course was chronic. Many patients had persistent lesions for more than 9 months; however, the number of papules tended to wax and wane with time. Although the cause of this eruption is unknown, it is sufficiently distinct and frequent to be recognized by clinicians as a cutaneous sign of human retrovirus infection.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Cytotoxicity of human serum for Leishmania donovani amastigotes: antibody facilitation of alternate complement pathway-mediated killing.

Mechanisms that mediate recovery from leishmanial infection have not been fully characterized but are generally believed to involve interactions between T lymphocytes and macrophages. A major role for serum-mediated effector mechanisms in the protection of humans from reinfection with Leishmania, however, has not been ruled out. In this report, amastigotes of L. donovani were incubated with dilutions of serum from normal subjects and from patients with kala-azar. Normal serum was cytotoxic for parasites at a dilution of greater than or equal to 1:20. Cytotoxicity did not occur in the presence of EDTA, was abolished by heating serum to 56 degrees C for 30 min, and was not diminished by prior adsorption of normal serum with parasites at 0 degree C. Killing proceeded normally in the presence of magnesium-ethylene glycol-bis(beta-aminoethyl ether)-N, N-tetraacetic acid, however, and was fully effected by C2-deficient serum. These studies indicated that killing of amastigotes, unlike that of promastigotes, was mediated via the alternate pathway of serum complement. In further studies, cytotoxicity of normal serum was enhanced three- to fivefold by factors in patient serum. This enhanced cytotoxicity also proceeded via the alternate complement pathway. Factors that enhanced cytotoxicity were characterized as parasite-specific immunoglobulin G: they eluted with immunoglobulin G on column chromatography, were adsorbed by immobilized staphylococcal protein A, and were not removed from the parasite surface by extensive washing. Thus, infection of individuals with L. donovani resulted in the production of a new, qualitatively and quantitatively distinct immune mechanism directed against the amastigote form of the parasite, namely, antibody-directed, alternate complement pathway-mediated cytotoxicity. These results provide a mechanistic framework for a role of humoral factors in human resistance to reinfection with L. donovani.

Animals↗
PubMed1985

Differential inhibition of macrophage microbicidal activity by liposomes.

In vitro culture of murine resident peritoneal macrophages with lymphokine (LK)-rich leukocyte culture fluids induces enhanced microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica. Macrophages infected with Leishmania and treated with LKs after infection acquire the capacity to kill the intracellular parasite within 72 h. When compared with control macrophage cultures treated with medium lacking LKs, 80 to 90% fewer macrophages treated with LKs contained amastigotes. In experiments designed to test liposome delivery of LKs to infected macrophages, addition of multilamellar liposomes composed of phosphatidylcholine and phosphatidylserine (molar ratio, 7:3) completely abrogated LK-induced microbicidal activity. Liposomes containing only phosphatidylcholine were not inhibitory. Inhibition of LK activity by the liposomes occurred regardless of whether the liposomes contained LKs. Liposomal inhibition of activated macrophage effector activity was limited to intracellular killing; LK-induced macrophage extracellular cytolysis (i.e., tumor cytotoxicity) was not affected by liposome treatment. These data indicate that elucidation of the effects of liposome composition on acquired host defense mechanisms may be useful for the design of drug delivery systems that allow expression or augmentation of immunologically induced mechanisms for the intracellular destruction of infectious agents.

Animals↗
PubMed1985

Macrophage activation to kill Leishmania major: activation of macrophages for intracellular destruction of amastigotes can be induced by both recombinant interferon-gamma and non-interferon lymphokines.

Macrophages treated with lymphokine (LK)-rich culture fluids from antigen- or mitogen-stimulated spleen cells or the hybridoma T cell 24/G1, or murine recombinant interferon-gamma (IFN-gamma) from either transfected monkey kidney cells (cos rIFN-gamma) or bacterial (E. coli) DNA (rIFN-gamma) developed the capacity to kill intracellular amastigotes of Leishmania major. Removal of IFN activity from LK by neutralizing fluid phase monoclonal anti-rIFN-gamma antibody, or by solid phase immunoadsorption, left residual macrophage activation factors that induced approximately 50% of the macrophage anti-leishmanial activity of untreated LK. In contrast, rIFN-gamma subjected to the same antibody treatments lost all capacity to induce this macrophage effector function. These results suggest that the intracellular destruction of amastigotes is regulated by several different factors. One of these factors is clearly IFN-gamma, which is pleiotropic in its effects on macrophage functions. The other non-IFN LK factors are immunochemically unrelated to IFN-gamma, and may regulate macrophage microbicidal activities in a more selective manner.

Animals↗
PubMed1985

Macrophage activation for microbicidal activity against Leishmania major: inhibition of lymphokine activation by phosphatidylcholine-phosphatidylserine liposomes.

Resident peritoneal macrophages from untreated mice develop microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica (current nomenclature = Leishmania major) after in vitro exposure to LK from antigen-stimulated leukocyte culture fluids. This LK-induced macrophage microbicidal activity was completely abrogated by addition of 7:3 phosphatidylcholine: phosphatidylserine liposomes. Liposome inhibition was not due to direct toxic effects against the parasite or macrophage effector cell; factors in LK that induce macrophage microbicidal activity were not adsorbed or destroyed by liposome treatment. Other phagocytic particles, such as latex beads, had no effect on microbicidal activity. Moreover, liposome inhibition of activated macrophage effector function was relatively selective: LK-induced macrophage tumoricidal activity was not affected by liposome treatment. Liposome inhibition was dependent upon liposome dose (5 nmoles/culture) and time of addition of leishmania-infected, LK-treated macrophage cultures. Addition of liposomes through the initial 8 hr of culture completely inhibited LK-induced macrophage microbicidal activity; liposomes added after 16 hr had no effect. Similarly, microbicidal activity by macrophages activated in vivo by BCG or Corynebacterium parvum was not affected by liposome treatment. Liposome treatment also did not affect the increased resistance to infection induced in macrophages by LK. These data suggest that liposomes interfere with one or more early events in the induction of activated macrophages (macrophage-LK interaction) and not with the cytotoxic mechanism itself (parasite-macrophage interaction). These studies add to the growing body of data that implicate cell lipid in regulatory events controlling macrophage effector function.

Animals↗
PubMed1985

Complement-mediated serum cytotoxicity for Leishmania major amastigotes: killing by serum deficient in early components of the membrane attack complex.

Leishmania major, the agent of Oriental sore, is an obligate intracellular parasite of macrophages in mammalian hosts. Man's immune defense against this organism requires participation of specifically sensitized lymphocytes and activated macrophages. Recent studies, however, have demonstrated that as little as 1/120 concentration of normal human serum is highly cytotoxic for the amastigote form of L. major. Initiation of the lethal process occurs rapidly, requiring only 30 sec of parasite exposure to serum, and is mediated by antibody-independent activation of the alternate complement pathway. The molecular mechanism of cytotoxicity is not known, but may require participation of the membrane attack complex, C5b-9. We investigated this possibility by treating amastigotes with human sera genetically deficient in complement components C5, 6, 7, 8, or 9. We then measured viability of treated parasites by amastigote-promastigote conversion. Our results were quite unexpected: not only did C9-deficient serum kill organisms, but sera singly deficient in each of the preceding components C6 to C8 were also cytotoxic. The degree of cytotoxicity was related both to serum concentration and to the point in the complement cascade at which deficiency occurred. Sera lacking C6 or C7 were less cytotoxic than those deficient in C8, which were less toxic than those deficient in C9. Cytoxicity of deficient sera was abolished by heating serum to 56 degrees C for 30 min. These findings indicate that an incomplete membrane attack complex may mediate cytotoxicity for L. major amastigotes. Moreover, our results raise important questions regarding the mechanism by which the complex is assembled on the surface of a living, unicellular eukaryotic organism.

Animals↗
PubMed1984

Defective spontaneous but normal antibody-dependent cytotoxicity for an extracellular protozoan parasite, Giardia lamblia, by C3H/HeJ mouse macrophages.

To understand murine host responses to extracellular protozoa, the capacity of peritoneal macrophages to exhibit cytotoxicity for [3H]thymidine-labeled Giardia lamblia trophozoites was investigated. Resident peritoneal macrophages from C3H/HeN mice expressed spontaneous cytotoxicity for G. lamblia in a manner that was dependent on both time and effector cell number; this cytotoxic activity was increased with cells elicited by an intraperitoneal injection of thio-glycollate. In contrast, spontaneous cytotoxicity for G. lamblia by resident and thioglycollate-elicited peritoneal macrophages from C3H/HeJ mice was markedly reduced. In the presence of anti-G. lamblia serum (ADCC), however, peritoneal macrophages from both C3H/HeN and C3H/HeJ mice exhibited striking augmentation of their cytotoxic activity for G. lamblia to equivalent levels. We conclude that macrophages from C3H/HeJ mice express defective spontaneous cytotoxicity but normal ADCC for the extracellular protozoan parasite, G. lamblia. The dissociation between the expression of these two effector cell functions suggests that macrophage spontaneous cytotoxicity and ADCC for extracellular protozoa are mediated by separate macrophage functions.

Animals↗
PubMed1984

Genetic control of macrophage activation for killing of extracellular targets.

Activated peritoneal macrophages from Corynebacterium parvum-treated mice of most inbred strains, including C57BL/6J (B), are cytotoxic to adherent 1023 sarcoma target cells as well as to larvae of Schistosoma mansoni. Macrophages from A/J (A) strain mice, on the other hand, are defective in this function. Segregation analysis of these two traits was compatible with the hypothesis that effective activation is, in each case, controlled by a single, dominant, autosomal gene. Typing of individual animals of the segregating backcross progeny and of AXB/BXA recombinant inbred strains for the expression of macrophage activation for tumoricidal and schistosomulicidal activity indicates that the genetic control of these two traits is closely linked or identical.

Animals↗
PubMed1984

Macrophages in resistance to rickettsial infections: protection against lethal Rickettsia tsutsugamushi infections by treatment of mice with macrophage-activating agents.

Peritoneal macrophages of BALB/c and C3H/HeN mice activated in vivo by intraperitoneal inoculation of viable Mycobacterium bovis strain BCG or the nonliving macrophage-activating agent Propionibacterium acnes (Corynebacterium parvum), were resistant to infection with Rickettsia tsutsugamushi, and they killed bacteria that did gain entry into the intracellular environment of these cells. This macrophage resistance to infection and intracellular destruction of rickettsiae was dependent upon development of an immune response to the activating agents, since macrophages elicited by sterile inflammatory agents failed to display either microbicidal activity unless cells were exposed to factors present in lymphokine-rich culture fluids from antigen or mitogen stimulated spleen cells (LK) in vitro. C3H/HeN mice that had been treated with activating agents, but not sterile inflammatory irritants, also survived intraperitoneal inoculation of up to 10(4) R. tsutsugamushi. This nonspecific protection required the chronic presence of activated macrophages: acute immune response induced by intraperitoneal injection of PPD into mice inoculated intradermally with BCG, or intraperitoneal inoculation of conconavalin A, were not sufficient to induce survival of rickettsial disease, although macrophages from these animals were activated to kill rickettsiae at the time of challenge. The critical nature of activated macrophages in nonspecific protection against rickettsial infection was demonstrated with the macrophage-defective C3H/HeJ mice. These mice are equally as susceptible as C3H/HeN mice to intraperitoneal inoculation of R. tsutsugamushi, but do not develop activated macrophages in response to BCG infection, and are not protected against lethal rickettsial challenge following BCG treatment.

Animals↗
PubMed1984

Functional characterization of lymphokines from the EL-4 T cell line that activate macrophages for nonspecific tumor cytotoxicity.

Culture fluids from a phorbol myristate acetate-stimulated EL-4 thymoma cell line were previously found to activate mouse macrophages to become nonspecifically tumoricidal. By gel filtration, 23,000- and 45,000-MW peaks were identified. In this study we compared EL-4 culture fluid activity with that obtained from antigen-stimulated mouse spleen cells. By four criteria, functional activity from the two sources was comparable: 1) Macrophage activation could be separated temporally into two steps, priming and triggering. 2) Macrophages activated by the fluids exhibited peak cytotoxic activity within 5-9 hr; no cytotoxic activity was demonstrable if addition of target cells was delayed 14 hr. 3) Mouse peritoneal exudate macrophages, but not resident macrophages, became cytotoxic after a 5-hr incubation with culture fluids. 4) Macrophages from certain strains of mice were incapable of activation; the same pattern of strain unresponsiveness was observed with both EL-4 and spleen cell culture fluids. Thus, it is likely that the two EL-4 products and the mouse spleen cell lymphokine activate the same cytotoxic mechanism.

Animals↗
PubMed1984

Activation of macrophages to kill rickettsiae and Leishmania: dissociation of intracellular microbicidal activities and extracellular destruction of neoplastic and helminth targets.

Mononuclear phagocytes undergo dramatic changes during differentiation from bone marrow stem cells to resident tissue macrophages. Throughout differentiation, cells lose or acquire numerous morphologic, metabolic and functional capacities such that mature, resident macrophages of one tissue often bear little resemblance to resident cells of another. Superimposed on the intrinsic continuum of mononuclear phagocyte differentiation are the reactive changes in macrophages induced by endogenous and exogenous stimuli: the ability of mononuclear phagocytes to respond to a particular stimulus may also change with cell differentiation. This dynamic interaction of cell differentiation and response to a micro-environment, and the resulting heterogeneity among mononuclear phagocytes for many functional characteristics, is clearly illustrated by the effector activities of activated macrophages that we describe in this report. Despite the common regulatory events for induction and expression of transient nonspecific cytotoxic reactions effective against such diverse targets as rickettsiae, leishmania, schistosomula, and neoplastic cells, these effector functions can be dissociated by the cells that perform the effector activity, and the signals that regulate these activities. The differential susceptibility of the various targets to particular killing mechanisms induced by LK in responsive populations only adds to the complexity of these in vitro analyses. The details of effector functions of activated macrophages are unique for each target.

Animals↗