Interferon-gamma in infection and immunoparalysis.
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
H W Murray
Publications and source records attributed to H W Murray.
Current and future clinical applications of interferon-gamma in host antimicrobial defense.
The T cell-derived macrophage-activating lymphokine, interferon-gamma (IFN-gamma), is the most broadly acting antimicrobial-inducing and host defense-enhancing cytokine thus far identified in experimental models of infectious diseases. The activity induced by IFN-gamma encompasses all classes of non-viral pathogens including intracellular and extracellular parasites, fungi and bacteria. In man, treatment with immuno-enhancing doses of IFN-gamma is safe, well-tolerated and stimulates the antimicrobial mechanisms of blood monocytes, circulating neutrophils and tissue macrophages. Aerosol administration activates alveolar macrophages in a compartmentalized fashion. Monocytes from IFN-gamma-treated patients with cancer, leprosy, and AIDS all respond with the activated phenotype, and suppressed monocyte HLA-DR expression in trauma patients can be up-regulated by IFN-gamma therapy. Thus far, IFN-gamma has been recognized as effective in the prophylaxis of chronic granulomatous disease and as adjunctive treatment in at least one systemic intracellular infection, visceral leishmaniasis. Additional trials suggest beneficial effects as prophylaxis in trauma and as treatment in leprosy, cutaneous leishmaniasis, and HIV- and non-HIV-related disseminated atypical mycobacterial infection. IFN-gamma is also being tested as a prophylaxis in patients with burns and advanced HIV infection and as an adjunct in drug-resistant tuberculosis. Future antimicrobial applications for IFN-gamma include: a) long-term prophylaxis in T cell-deficient states, b) short-term prophylaxis in patients with a reversible host defense defect such as granulocytopenia or immune response suppression induced by trauma or burn injury, and c) adjunctive treatment along with conventional antibiotic therapy for i) nosocomial pneumonia (aerosol administration), ii) opportunistic infections in general, iii) infections which typically respond poorly to available treatment and iv) for infections which require prolonged therapy for cure. In the latter, the addition of IFN-gamma may accelerate the response to conventional therapy and permit a clinically important reduction in the duration of treatment while preserving efficacy.
Animals↗
Delivery of human interferon-gamma via gene transfer in vitro: prolonged expression and induction of macrophage antimicrobial activity.
Daily parenteral administration of exogenous interferon-gamma (IFN-gamma) induces or accelerates recovery in experimental and human infections. To develop an alternative delivery system, a replication-defective recombinant adenovirus expressing human IFN-gamma was constructed. The complete coding region of IFN-gamma was amplified by RT-PCR and inserted into an adenovirus cloning vector under the control of a human cytomegalovirus promoter. Recombinant adenovirus containing the IFN-gamma minigene (dAv-IFN-gamma) was isolated from 293 cells co-transfected with the linearized plasmid and an E1 region-deleted fragment of adenovirus genome. Following in vitro infection with dAv-IFN-gamma, dose-dependent and time-dependent expression of IFN-gamma, mRNA and production of soluble protein were demonstrated in human diploid fibroblat and HeLa cell cultures by Northern blot and ELISA, respectively. Extracellular protein secretion persisted for > = 4 weeks following initial transfection, and secreted IFN-gamma induced both antiviral activity (8000-25,000 U/ml) and macrophage activation with killing of intracellular Toxoplasma gondii and leishmania donovani. These results establish that dAv-IFN-gamma generates long-term secretion of biologically active IFN-gamma in vitro and suggest that this vector may be a useful delivery system for cytokine therapy.
Adenoviridae↗
Cure of antimony-unresponsive Indian visceral leishmaniasis with amphotericin B lipid complex.
Twenty-one Indian patients with visceral leishmaniasis who did not respond to or relapsed after 28-60 days of pentavalent antimony therapy were treated with amphotericin B lipid complex (ABLC). Five infusions (3 mg/kg each) given every second day over 9 days (total dose, 15 mg/kg) resulted in a 100% apparent cure response. In 4 other patients who had not responded to antimony, apparent cure was also induced by ABLC given 3 mg/kg a day 5 consecutive days (total dose, 15 mg/kg). Fever and chills developed routinely during the initial 2-h infusions; these reactions were tolerated and diminished with successive infusions. Six months after treatment, all 25 patients were healthy, had parasite-free bone marrow aspirates, and were considered cured. ABLC is effective short-course therapy for kala-azar patients who do not respond to conventional antimony treatment.
Adolescent↗
Models of relapse of experimental visceral leishmaniasis.
To establish models for studying recurrence of visceral leishmaniasis, a growing problem in T cell-deficient patients, two approaches were investigated: treatment of euthymic BALB/c mice with quiescent Leishmania donovani infection with T cell-depleting or anti-cytokine antibodies and serial observation of acutely infected nude BALB/c mice after an initial antileishmanial response induced by amphotericin B treatment. In chronically infected euthymic mice, maintenance of acquired immunity and prevention of relapse required CD4 cells and a multicytokine-dependent mechanism involving endogenous interleukin-2, interferon-gamma, and tumor necrosis factor-alpha. Acutely infected nude mice responded to amphotericin B with a > or = 85% reduction in liver parasite burdens; however, after a brief lag, visceral infection readily recurred in the posttreatment period. Both models may be useful for testing experimental interventions designed to reduce relapse of previously controlled visceral leishmaniasis in T cell-deficient hosts.
Animals↗
Induction of macrophage antiprotozoal activity by monocyte chemotactic and activating factor.
To determine if monocyte chemotactic and activating factor (MCAF) induces intracellular antimicrobial activity, human monocyte-derived macrophages were treated with MCAF and challenged with Toxoplasma gondii and Leishmania donovani. Pretreatment with MCAF induced macrophages to inhibit protozoal replication by approximately 50%. These findings suggest a potential host defense role for MCAF in the inflammatory response to intracellular pathogens.
Animals↗
Activity of oral atovaquone alone and in combination with antimony in experimental visceral leishmaniasis.
BALB/c mice with established visceral infection caused by the intracellular protozoan Leishmania donovani were treated with oral atovaquone for 7 days. Treatment with 100 mg/kg of body weight per day was optimal and halted parasite replication in the liver. In mice treated with atovaquone, the effect of a suboptimal dose of pentavalent antimony was converted from partially leishmanistatic to leishmanicidal. These results demonstrate the in vivo antileishmanial effect of atovaquone and suggest a potential role for this oral agent in visceral leishmaniasis as an adjunct to conventional antimony treatment.
Administration, Oral↗
Multiple host defense defects in failure of C57BL/6 ep/ep (pale ear) mice to resolve visceral Leishmania donovani infection.
Euthymic C57BL/L ep/ep (pale ear [PE]) mice halt the visceral replication of intracellular Leishmania donovani but fail to properly resolve infection. A previous study identified an isolated defect in tissue granuloma formation in these mice; CD4+ and CD8+ cell number, gamma interferon (IFN-gamma) production, and macrophage antimicrobial activity in vitro were all intact. New in vivo results reported here suggest a considerably more complex immune defect, with evidence indicating (i) enhanced control over L. donovani after transfer of normal C57BL/6 spleen cells, (ii) a partially suppressive Th2 cell-associated response mediated by interleukin-4 (IL-4) but not reversed by CD4+ cell depletion, (iii) absent responses to endogenous Th1 cell lymphokines (IFN-gamma and IL-2) but preserved responsiveness to endogenous tumor necrosis factor alpha, (iv) absent responses to exogenous treatment with recognized antileishmanial cytokines (IFN-gamma, IL-2, IL-12, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) not corrected by transfer of C57BL/6 spleen cells, and (v) a deficient response to antimony chemotherapy. Defective hepatic granuloma formation was not corrected by transfer of C57BL/6 spleen cells or by anti-IL-4 administration. While treatment with IL-2 and GM-CSF modified the tissue reaction and induced selected effector cells to encase tissue macrophages, no antileishmanial activity resulted. Together, these observations suggest that the failure of PE mice to resolve visceral L. donovani infection likely represents expression of multiple suboptimal immune responses and/or partial defects, probably involving a combination of T-cell dysfunction, a Th2 cell response, and target cell (macrophage) hyporesponsiveness.
Amphotericin B↗
Pentavalent antimony-mannan conjugate therapy of experimental visceral leishmaniasis.
Pentavalent antimony-mannan (Sb[V]-mannan) was 10-fold more potent than sodium stibogluconate in a murine model of visceral leishmaniasis. Liver antimony concentrations were six-fold higher after Sb[V]-mannan therapy compared with a dose of sodium stibogluconate that was equipotent in reducing liver parasite burdens. Murine toxicity of Sb[V]-mannan was variable, with a 50% lethal dose (LD50) for one preparation that was well above the concentration that killed 90% of the parasites, and for another preparation was only modestly higher than the concentration that killed 90% of the parasites.
Animals↗
Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis.
When administered at or near the initiation of experimental intracellular infection caused by Leishmania major, Toxoplasma gondii, or Cryptococcus neoformans, treatment with the immuno-regulatory cytokine interleukin 12 (IL-12), induces protective antimicrobial activity. In contrast, once infections are established, IL-12 exerts considerably less or no effect in the face of a suppressive Th2 cell-associated response (L. major) or rapidly progressive fatal infection (T. gondii). To test the efficacy of IL-12 in an established intracellular protozoal infection but under quite different immunologic conditions (Th1 cell response, acquired resistance), L. donovani-infected BALB/c mice were treated starting 2 wk after challenge coincident with the onset of the Th1 cell response. In this environment, 7 d of IL-12 treatment reduced liver parasite burdens by 47%, an effect comparable to that induced by exogenous interferon (IFN) gamma. The in vivo mechanism responsive to IL-12 was complex, and required both CD4+ and CD8+ T cells as well as natural killer cells and the action of multiple endogenous antileishmanial cytokines (IFN-gamma, IL-2, tumor necrosis factor alpha). Early treatment with IL-12 before the expression of the Th1 cell response was also effective and induced an accelerated, near-cure response via an IFN-gamma-dependent mechanism. These results extend the antimicrobial-inducing capacity of IL-12 beyond prophylaxis by indicating that IL-12 can exert clear-cut therapeutic activity in an established intracellular infection.
Animals↗
Immunochemotherapy for a systemic intracellular infection: accelerated response using interferon-gamma in visceral leishmaniasis.
To determine if cytokine immunotherapy accelerates the response to conventional treatment in visceral leishmaniasis (kala-azar), previously untreated Indian patients were given antimony for 30 days (n = 15) or antimony plus interferon-gamma (IFN-gamma; n = 16). After 10 days, 10 (63%) of 16 patients treated with antimony plus IFN-gamma versus 1 (7%) of 15 randomized to antimony alone were considered cured of parasites (P < .005). On day 20, 14 (93%) of 15 versus 6 (40%) of 15 patients, respectively, were apparent clinical cures (P < .006), and treatment was discontinued early in the 14 IFN-gamma treated responders. Day 30 apparent cure rates (100% vs. 73%) and 6-month ultimate cure responses (87% vs. 60%) were higher in IFN-gamma-treated patients but not statistically different from controls (P > .05). All 13 IFN-gamma-treated subjects who were cured (12 of whom received therapy for 20 days) have remained healthy with follow-up of 14-24 months (mean, 18.9). These results indicate that IFN-gamma successfully accelerates the parasitologic and clinical response to antimony treatment, an effect that should permit shortening the duration of conventional therapy in previously untreated kala-azar.
Adolescent↗
Antimicrobial response of a T cell-deficient host to cytokine therapy: effect of interferon-gamma in experimental visceral leishmaniasis in nude mice.
To determine if interferon (IFN)-gamma can enhance intracellular antimicrobial defense in a T cell-deficient host, nude BALB/c mice were infected with Leishmania donovani and treated with IFN-gamma. IFN-gamma induced killing of L. donovani in livers of euthymic mice but had no effect in nude mice despite activating peritoneal macrophages in vivo. Transfer of CD4+ or CD8+ T cells permitted nude mice to respond to IFN-gamma; treatment with T cell-regulated antileishmanial cytokines (interleukin-2, granulocyte-macrophage colony-stimulating factor, or tumor necrosis factor-alpha) could not substitute for T cells. NK cells played no apparent role. In reconstituted nude mice, the antileishmanial effect of IFN-gamma correlated with markedly enhanced mononuclear cell recruitment to infected liver foci. Thus, although IFN-gamma activates macrophages in the absence of host T cells, a T cell mechanism is required for antileishmanial activity in tissue. Provided one T cell subset is adequately preserved, IFN-gamma may prove useful in intracellular infections in the T cell-deficient host.
Animals↗
Stavudine in patients with AIDS and AIDS-related complex: AIDS clinical trials group 089.
In a phase I trial of stavudine in AIDS or AIDS-related complex (ARC), antiviral effects and safety were assessed in 41 patients treated with dosages of 0.5-12.0 mg/kg/day. Among evaluable patients, 10% increases in CD4 lymphocyte counts were sustained in 24 (60%) of 40 during treatment; an NAUC response (normalized area under the CD4 cell count-versus-time curve > 1.0) was observed in 31 (91%) of 34 at 10 weeks and in 20 (80%) of 25 at 24 weeks; 15 (83%) of 18 had decreases in p24 antigenemia; and 24 (60%) of 40 gained > or = 2.5 kg body weight. Median CD4 lymphocyte levels remained above baseline for 6 months in patients receiving > 0.5 mg/kg/day. Median serum p24 antigen levels remained below baseline for > or = 1 year in patients with p24 antigen responses. The principal toxicity was peripheral neuropathy, which generally resolved after drug discontinuation but limited the dosage to < or = 2.0 mg/kg/day. Additional trials assessing the effect of stavudine on overall morbidity and mortality are ongoing.
AIDS-Related Complex↗
Effect of treatment with interferon-gamma alone in visceral leishmaniasis.
Interferon-gamma (IFN-gamma) enhances the therapeutic response to pentavalent antimony in patients with visceral leishmaniasis. To determine the effect of cytokine immunotherapy alone, 9 patients with kala-azar were treated with IFN-gamma before receiving antimony. After 20 days of IFN-gamma therapy, 4 patients showed no parasitologic response; in the remaining 5 patients, however, splenic aspirate parasite scores declined from 4.2 +/- 0.2 to 1.2 +/- 0.5 (mean +/- SE). These results indicate that treatment with IFN-gamma alone can induce visceral antileishmanial activity. However, the limited efficacy in this uncontrolled pilot trial suggests that the therapeutic role of IFN-gamma in kala-azar is that of an adjunct to conventional antimony treatment.
Adult↗
Effect of granulocyte-macrophage colony-stimulating factor in experimental visceral leishmaniasis.
GM-CSF induces three effects potentially beneficial in visceral leishmaniasis: blood monocyte mobilization, macrophage activation, and amelioration of granulocytopenia. To determine the experimental role and effect of GM-CSF in this intracellular infection, livers from Leishmania donovani-infected BALB/c mice were tested for GM-CSF mRNA expression and mice were treated with anti-GM-CSF antiserum or GM-CSF. L. donovani infection upregulated hepatic GM-CSF mRNA expression by 10-fold, and anti-GM-CSF treatment exacerbated visceral infection and tripled liver parasite burdens 4 wk after challenge. In euthymic mice with established infection, treatment with 1-5 micrograms/d murine GM-CSF induced three dose-related effects: peripheral blood leukocytosis, preferential accumulation of myelomonocytic cells at visceral foci of infection, and leishmanicidal activity comparable to that achieved by IFN-gamma. These effects were either largely or entirely T cell dependent. Treatment with human GM-CSF also induced anti-leishmanial activity but with little effect on peripheral leukocyte number or tissue myelomonocytic cell influx; human G-CSF stimulated marked peripheral granulocytosis and neutrophil tissue accumulation but induced little antileishmanial effect. These results identify a role for endogenous GM-CSF in the initial host defense response to L. donovani, reemphasize the influxing monocyte as an effector cell, and indicate that GM-CSF can be used as an antileishmanial treatment.
Animals↗
Gamma interferon in the treatment of Kala-azar and other forms of Leishmaniasis.
Explore the source record for details and available documents.
Antiprotozoal Agents↗
Onchocerciasis in New York City. The Moa-Manhattan connection.
When faced with a patient with travel-associated dermatitis, clinicians often diagnose and treat for a suspected hypersensitivity reaction or infestation with an ectoparasite. We studied a small cluster of travelers from New York, NY, to the Moa River in Sierra Leone who developed dermatitis caused by Onchocerca volvulus. Our patients had relatively long stays in an endemic area and numerous bites by blackflies. Such patients represent a subset of travelers in whom dermatitis should prompt evaluation for onchocerciasis.
Adult↗
Role and effect of TNF-alpha in experimental visceral leishmaniasis.
TNF-alpha has been implicated in cytokine-induced macrophage activation and tissue granuloma formation, two activities linked to control of intracellular visceral infection caused by Leishmania donovani. To determine the role of TNF-alpha in L. donovani-infected BALB/c mice, we measured TNF-alpha levels and treated mice with either anti-TNF-alpha antiserum or TNF-alpha. TNF-alpha activity in infected livers was increased by 2.7-fold 2 wk after challenge and by 5.5-fold at wk 8. In parallel, although control mice acquired resistance by wk 4 and resolved infection by wk 8, liver parasite burdens steadily increased in anti-TNF-alpha-treated animals. Hepatic granuloma formation, however, was not impaired by anti-TNF-alpha. Endogenous TNF-alpha levels provoked by L. donovani appeared sufficient and optimal because exogenous TNF-alpha administration had no beneficial effect on established infection and continuous high-dose treatment impaired antileishmanial activity. Thus, although not required for granuloma formation, endogenous TNF-alpha appears to be critical to both initial acquisition of resistance to L. donovani and resolution of experimental visceral infection.
Animals↗