Biomedical subjects

F Modabber

Publications and source records attributed to F Modabber.

At least 19 recordsLinked to original sources

PubMed2005

Dichotomy of protective cellular immune responses to human visceral leishmaniasis.

Healing/protective responses in human visceral leishmaniasis (VL) are associated with stimulation/production of Th1 cytokines, such as interferon IFN-gamma, and conversion in the leishmanin skin test (LST). Such responses were studied for 90 days in 44 adult healthy volunteers from VL non-endemic areas, with no past history of VL/cutaneous leishmaniasis (CL) and LST non-reactivity following injection with one of four doses of Alum-precipitated autoclaved Leishmania major (Alum/ALM) +/- bacille Calmette-Guerin (BCG), a VL candidate vaccine. The vaccine was well tolerated with minimal localized side-effects and without an increase in antileishmanial antibodies or interleukin (IL)-5. Five volunteers (5/44; 11.4%) had significant IFN-gamma production by peripheral blood mononuclear cells (PBMCs) in response to Leishmania antigens in their prevaccination samples (P = 0.001) but were LST non-reactive. On day 45, more than half the volunteers (26/44; 59.0%) had significantly high LST indurations (mean 9.2 +/- 2.7 mm) and high IFN-gamma levels (mean 1008 +/- 395; median 1247 pg/ml). Five volunteers had significant L. donovani antigen-induced IFN-gamma production (mean 873 +/- 290; median 902; P = 0.001), but were non-reactive in LST. An additional five volunteers (5/44; 11.4%) had low IFN-gamma levels (mean 110 +/- 124 pg/ml; median 80) and were non-reactive in LST (induration = 00 mm). The remaining eight volunteers had low IFN-gamma levels, but significant LST induration (mean 10 +/- 2.9 mm; median 11). By day 90 the majority of volunteers (27/44; 61.4%) had significant LST induration (mean 10.8 +/- 9.9 mm; P < 0.001), but low levels of L. donovani antigen-induced IFN-gamma (mean 66.0 +/- 62 pg/ml; P > 0.05). Eleven volunteers (11/44; 25%) had significantly high levels of IFN-gamma and LST induration, while five volunteers had low levels of IFN-gamma (<100 pg/ml) and no LST reactivity (00 mm). One volunteer was lost to follow-up. In conclusion, it is hypothesized that cellular immune responses to human VL are dichotomatous, and that IFN-gamma production and the LST response are not in a causal relationship. Following vaccination and probably cure of VL infection, the IFN-gamma response declines with time while the LST response persists. LST is a simple test that can be used to assess candidate vaccine efficacy.

Adult↗

PubMed2003

Treatment of cutaneous leishmaniasis with aminosidine (paromomycin) ointment: double-blind, randomized trial in the Islamic Republic of Iran.

OBJECTIVE: To compare the parasitological and clinical efficacy of four weeks versus two weeks of treatment with aminosidine (paromomycin) ointment in patients with cutaneous leishmaniasis caused by Leishmania major in the Islamic Republic of Iran. METHODS: Double-blind, randomized trial of four weeks of aminosidine ointment (n = 108) vs two weeks of aminosidine ointment and two weeks of placebo (n = 108). Patients were assessed on days 15, 29, 45, and 105 for clinical cures and clinical and parasitological cures. FINDINGS: Four weeks' treatment gave significantly better cure rates than two weeks' treatment: on day 29, there were 80/108 (74%) vs 64/108 (59%) clinical cures (P = 0.05) and 47 (44%) vs 26 (24%) clinical and parasitological cures (P = 0.005). By day 45, fewer patients who received four weeks' treatment had required rescue treatment with antimonials than those who received two weeks' treatment: 20 (19%) vs 36 (33%) (P = 0.02). On day 105, the results still favoured those who had been allocated four weeks of active treatment, but the differences were no longer as clearly significant. No side-effects were observed or reported. CONCLUSION: Approximately two-thirds of patients given ointment for four weeks were cured clinically. Although about half of those cured might have recovered spontaneously even without treatment, four weeks of aminosidine ointment could become the first-line treatment for uncomplicated cutaneous leishmaniasis due to L. major, with antimonials needed in only the one-third of patients not cured by the end of treatment with aminosidine. This would considerably reduce the costs and side-effects associated with antimonial drugs.

Antiprotozoal Agents↗

PubMed2003

Immune response measured in human volunteers vaccinated with autoclaved Leishmania major vaccine mixed with low dose of BCG.

The immune responses induced against Leishmania antigens in volunteers who were vaccinated in a double-blind, randomized field efficacy trial of a preparation of autoclaved Leishmania major (ALM) mixed with a low dose of Bacille Calmette-Guerin vaccine (BCG) who developed either a cutaneous leishmaniasis (CL) lesion due to exposure to infected sandfly bite(s) or did not develop a lesion during the course of the trial were studied and compared with those of non-vaccinated controls. Blood samples were also assayed from different groups including volunteers with history of CL and volunteers with previous positive or negative leishmanin skin test (LST) without a history of CL. The vaccinated volunteers had received a single dose of either ALM mixed with a low dose of BCG or the same dose of BCG alone. The LST and in vitro proliferative response (stimulation index, SI), interferon gamma (IFN-gamma) production and, in a few cases, interleukin (IL)-4 production of peripheral blood mononuclear cells to soluble Leishmania antigens were measured. The results indicated that volunteers who developed CL in the vaccine arm showed a slightly higher SI than cases who received BCG alone. Volunteers with history of CL and volunteers with positive LST demonstrated the strongest proliferation indices and IFN-gamma production. The data suggest that a single dose of ALM + BCG induces a weak Th1 response in vaccinated volunteers that is far lower than that in volunteers with prior subclinical infection or volunteers with history of CL, who are presumed to be immune.

Adolescent↗

PubMed2001

Vervet monkeys vaccinated with killed Leishmania major parasites and interleukin-12 develop a type 1 immune response but are not protected against challenge infection.

Leishmania major is a protozoan parasite that causes chronic cutaneous lesions that often leave disfiguring scars. Infections in mice have demonstrated that leishmanial vaccines that include interleukin-12 (IL-12) as an adjuvant are able to induce protective immunity. In this study, we assessed the safety, immunopotency, and adjuvant potential of two doses of IL-12 when used with a killed L. major vaccine in vervet monkeys. The induction of cell-mediated immunity following vaccination was determined by measuring delayed-type hypersensitivity, in vitro lymphocyte proliferation, and gamma interferon (IFN-gamma) production. Protection was assessed by challenging the animals with L. major parasites and monitoring the course of infection. At low doses of IL-12 (10 microg), a small increase in the parameters of cell-mediated immunity was observed, relative to those in animals that received antigen without IL-12. However, none of these animals were protected against a challenge infection. At higher doses of IL-12 (30 microg), a substantial increase in Leishmania-specific immune responses was observed, and monkeys immunized with antigen and IL-12 exhibited an IFN-gamma response that was as great as that in animals that had resolved a primary infection and were immune. Nevertheless, despite the presence of correlates of protection, the disease course was only slightly altered, and protection was low compared to that in self-cured monkeys. These data suggest that protection against leishmaniasis may require more than the activation of Leishmania-specific IFN-gamma-producing T cells, which has important implications for designing a vaccine against leishmaniasis.

Animals↗

PubMed2000

Autoclaved Leishmania major vaccine for prevention of visceral leishmaniasis: a randomised, double-blind, BCG-controlled trial in Sudan.

BACKGROUND: Visceral leishmaniasis is a major cause of morbidity and mortality in the Sudan. Drug treatment is expensive, and drug resistance is becoming increasingly common. Safe, effective, and cheap vaccines are needed. We report the results of a vaccine trial against human visceral leishmaniasis. METHODS: We undertook a double-blind randomised trial to test the safety and efficacy of an autoclaved Leishmania major (ALM) promastigote vaccine (1 mg per dose). Of 5093 volunteers screened, 2306 had negative leishmanin skin tests and reciprocal titres of less than 6400 in the direct agglutination test. They were randomly assigned two doses of ALM mixed with BCG or BCG alone. Volunteers were followed up for 2 years. The primary endpoint was clinical visceral leishmaniasis or post-kala-azar dermal leishmaniasis. Analyses were by intention to treat. FINDINGS: Side-effects were confined to the injection site. The cumulative frequency of visceral leishmaniasis at 2 years did not differ significantly between the group assigned ALM plus BCG and that assigned BCG alone (133/1155 [11.5%] vs 141/1151 [12.3%], p=0.6). The vaccine efficacy was 6% (95% CI -18 to 25). The proportion of individuals showing leishmanin skin conversion was significantly higher in the ALM plus BCG group than in the BCG alone group throughout follow-up (303 [30%] vs 72 [7%] at 42 days). Individuals whose leishmanin test converted after vaccination (induration > or =5 mm) had a significantly lower frequency of visceral leishmaniasis than non-responders (27/375 [7.2%] vs 210/1660 [12.7%], p=0.003). INTERPRETATION: We found no evidence that two doses of ALM plus BCG offered significant protective immunity against visceral leishmaniasis compared with BCG alone. Leishmanin skin conversion with an induration of 5 mm or more in either group was associated with protection from the disease.

Adolescent↗

PubMed1999

A randomised, double-blind, controlled trial of a killed L. major vaccine plus BCG against zoonotic cutaneous leishmaniasis in Iran.

Safety and efficacy of killed (autoclaved) L. major promastigotes, ALM, mixed with BCG against zoonotic cutaneous leishmaniasis was tested in healthy volunteers (n = 2453) in a randomized double blind trial vs. BCG as control. Side-effects were similar in both groups but tended to be slightly more frequent and prolonged in the ALM + BCG group. Leishmanin skin test conversion (induration > or =5 mm) was significantly greater in the ALM + BCG than in the BCG group (36.2% vs. 7.9% on day-80 and 33% vs. 19%, after 1 year, respectively). Cumulative incidence rates for 2 years, were similar in both groups (18.0% vs. 18.5%). However, LST responders on day 80 (> or =5 mm) had a significantly lower incidence (35%) of CL during the first year than non-responders. A single dose of ALM + BCG is not sufficiently immunogenic to provide a measurable response when compared to BCG alone. A single dose of this vaccine has been shown to be safe with no evidence of an exacerbating response following natural infection; hence, multiple doses or other adjuvants should be considered to increase its immunogenicity.

Adolescent↗

PubMed1998

Randomised vaccine trial of single dose of killed Leishmania major plus BCG against anthroponotic cutaneous leishmaniasis in Bam, Iran.

BACKGROUND: A vaccine consisting of a single dose of whole-cell autoclave-killed Leishmania major (ALM) mixed with BCG was assessed in comparison with BCG alone against anthroponotic (human to human transmission) cutaneous leishmaniasis in a randomised double-blind trial in Bam, Iran. METHODS: 3637 schoolchildren, aged 6-15 years, with no history of cutaneous leishmaniasis and no response to a leishmanin skin test, were randomly assigned to receive 1 mg ALM mixed with BCG (n = 1839), or BCG alone (n = 1798). Safety of the vaccine and the incidence of confirmed cases of cutaneous leishmaniasis were followed up for 2 years. FINDINGS: Side-effects were those usually associated with BCG vaccination, but tended to persist longer in the ALM + BCG group. After exclusion of four cases occurring within 80 days of vaccination (one in the ALM + BCG group and three in the BCG group), the 2-year incidence of cutaneous leishmaniasis did not differ significantly between vaccine and BCG groups: 2.8% vs 3.3%, respectively (total cases 112). A sex-stratified analysis showed that in boys the vaccine conferred a protective efficacy of 18% and 78% for the first and second years, respectively--a crude 2-year overall protection of 55% (95% CI 19-75%, p < 0.01). In the first 9 months after vaccination, there was a non-significant excess of cases in the ALM + BCG group (25 vs 16), whereas the incidence of cutaneous leishmaniasis thereafter was significantly reduced in the ALM + BCG group (27 vs 44, p < 0.05). INTERPRETATION: A single dose of ALM + BCG was safe and more immunogenic than BCG alone, as measured by leishmanin skin test. The exact reason for the apparent protective effect of the vaccine in boys is unknown, and may be a chance finding. However, since boys are more exposed to the infection, which is indicated by higher disease prevalence in boys in this study population, the preferential protective effect in boys may have resulted from a greater booster effect produced by repeated exposure to infected sandflies. Booster injections or alternative adjuvants should be tried to improve the potential efficacy of this vaccine.

Adjuvants, Immunologic↗

PubMed1997

Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial.

BACKGROUND: Hundreds of thousands of cases of cutaneous leishmaniasis occur each year worldwide. Available therapies are parenteral, moderately toxic, and costly. OBJECTIVE: To determine the efficacy of and tolerance for oral allopurinol as monotherapy for cutaneous leishmaniasis. DESIGN: Randomized, controlled trial. SETTING: Outpatient clinics in 11 regions of Colombia in which cutaneous leishmaniasis is endemic. PATIENTS: 187 otherwise healthy adults with cutaneous leishmaniasis. Eighty-four percent of patients were infected with or were from regions with Leishmania panamensis; 16% were infected or were from regions with L. braziliensis. INTERVENTION: Patients were randomly assigned to one of three treatment groups. The first group received allopurinol, three 100-mg tablets four times daily (20 mg/kg of body weight per day) for 28 days. The second group received three placebo tablets four times daily for 28 days. The third group received Glucantime, 20 mg of intramuscular antimony/kg per day for 20 days. MEASUREMENT: Complete cure was defined as complete clinical reepithelialization of all lesions at 3 months and no relapse during 12 months of follow-up. RESULTS: Of 182 patients whose data could be analyzed, 157 (86%) were evaluated. In the allopurinol group, 18 of 55 (33% [95% CI, 21% to 47%]) patients were cured; in the placebo group, 17 of 46 patients (37% [CI, 23% to 52%]) were cured (difference, 4% [CI, -14% to 22%]; P = 0.68); and in the Glucantime group, 52 of 56 patients (93% [CI, 83% to 98%]) were cured (P < 0.001 compared with the allopurinol and placebo groups combined). In most cases, therapy was considered to have failed because the lesion did not reepithelialize by 1.5 months after the end of therapy. Three cases of relapse (two in the allopurinol group and one in the placebo group) at the nasal mucosa (mucosal leishmaniasis) had occurred by the end of 12 months of follow-up. CONCLUSIONS: Allopurinol monotherapy has no effect on Colombian cutaneous disease primarily caused by L. panamensis and therefore is unlikely to be effective against cutaneous leishmaniasis in other endemic regions.

Adult↗

PubMed1997

Efficacy of sodium stibogluconate alone and in combination with allopurinol for treatment of mucocutaneous leishmaniasis.

A randomized, open, controlled clinical trial was designed to evaluate the efficacy, tolerance, and safety of sodium stibogluconate plus allopurinol and sodium stibogluconate alone as treatment of patients with mucocutaneous leishmaniasis. In phase 1 of the study, all 22 patients with severe disease had improvement of their lesions, but only two had clinical cure (both of these patients received sodium stibogluconate alone). In phase 2, which included 59 patients with moderate disease, the cure rate among sodium stibogluconate recipients was 75% (21 of 28) compared with 63.6% (14 of 22) among the sodium stibogluconate plus allopurinol recipients. The rates of clinical adverse events were similar among both groups. Thrombocytopenia was more frequent in the sodium stibogluconate plus allopurinol recipients, but the difference was not statistically significant. Eight patients (two sodium stibogluconate recipients and six sodium stibogluconate plus allopurinol recipients) withdrew from the study because of severe thrombocytopenia. In this study, the addition of allopurinol to sodium stibogluconate provided no clinical benefit as treatment of mucocutaneous leishmaniasis.

Adult↗

PubMed1996

Progress on vaccines against parasites.

There has been significant progress in attempts to develop effective vaccines against parasitic diseases, including malaria, leishmaniasis and schistosomiasis. In malaria, in addition to field trials with SPf66, the Colombian malaria vaccine, several Plasmodium falciparum candidate vaccines are under Phase I testing, including NYVAC-7, a multi-antigen, attenuated recombinant vaccinia virus. Additional candidate antigens are at an advanced stage of pre-clinical development. In leishmaniasis, Phase III clinical trials on first generation vaccines (killed Leishmania, with or without BCG) are proceeding in several countries. Use of IL-12 as an adjuvant for use with killed Leishmania vaccine is being studied in non-human primates. A genetically constructed (gene knock-out) live avirulent Leishmania is being developed in preclinical studies as a potential live vaccine. Research is also underway to evaluate several recombinant proteins. The genes coding for such leading candidate antigens are also being incorporated into various live vectors to yield recombinant organisms with vaccination potential. In schistosomiasis, a strategy for the development of a vaccine against Schistosoma mansoni has been established, focussing on six priority recombinant antigens. An Asian S. japonicum vaccine development network has also been established, initially to develop a vaccine to block transmission in cattle and oxen, important reservoirs of the disease in Asia, and ultimately a human vaccine. As all of the above-mentioned vaccines will be used in the field in disease-endemic tropical countries, optimal stability will be of paramount importance.

Adjuvants, Immunologic↗

PubMed1995

Vaccines against leishmaniasis.

Unlike some other parasites, Leishmania can be grown in cell-free media with ease. This simple cultivation and the use of killed parasites as skin-test antigens (leishmanin) for diagnosis in humans during the past several decades have prompted scientists to try using the killed parasites, with or without adjuvant, as vaccines or for immunotherapy. In addition, different recombinant molecules, either parasite fractions or genetically engineered organisms (i.e. Leishmania made avirulent by removing specific genes, or bacteria carrying and expressing leishmanial genes), are being investigated as potential future vaccines against leishmaniasis. The 'first-generation' vaccines, composed of killed parasites with or without adjuvant, have been derived using an empirical approach. The 'second-generation' vaccines have been genetically constructed, using a more rational approach. At present, the first-generation vaccines are at various stages of Phase I (safety), II (reactivity) or III (efficacy) trials in humans. Results are expected in 1-2 years. The second-generation vaccines are, however, only in a preclinical state and are not expected to reach clinical trials for at least 3 years. The Special Programme for Research and Training in Tropical Diseases (TDR) is actively involved in most clinical trials of the first-generation vaccines and supports many of the second-generation candidates. In the present article, the advantages and disadvantages of each approach to vaccine development are discussed and the progress being made is briefly reviewed.

Animals↗

PubMed1990

Development of vaccines against leishmaniasis.

A vaccine against leishmaniasis is the only practical means to control this disease in many epidemiological situations. Two approaches have been adopted: pragmatic and systematic. The pragmatic approach involves trial of crude leishmanial components in animals and then in humans if they meet safety requirements. The systematic approach requires identification of the protective immunogen(s), appropriate carrier and adjuvant, and determination of the immune responses and modes of presentation of the immunogens to achieve the desired effect. Progress have been made with both approaches. Killed Leishmania promastigotes have been used in Brazil for high risk individuals with encouraging results. Impressive results have also been observed with killed Leishmania plus BCG for immunotherapy of cutaneous leishmaniasis in Venezuela. With the systematic approach, recent research has identified some protective immunogens, cloned protective murine T-cells, developed primate models resembling the human disease, cloned and expressed genes of some potential immunogens, identified some features of the protective immune response, determined modes of presentation of immunogen to produce a protective response, and been able to protect mice (even/Balb/c) against L. major infection. The difficult part that remains is the implementation of a vaccine or any control measure in the poor communities where they are needed and where the lack of required infrastructure does not allow adequate coverage.

Animals↗

PubMed1989

Experiences with vaccines against cutaneous leishmaniasis: of men and mice.

The need for a vaccine(s) against cutaneous leishmaniasis and the populations at risk for whom such vaccines should be developed are briefly discussed. The current human vaccine studies are reviewed, as are some experimental mouse studies with emphasis on Leishmania major infection relevant to vaccine development. Based on the information available from the mouse model and those data which are being sought in human studies, the benign nature of the cutaneous disease, the ease with which L. major can be manipulated to yield the required material, and the ongoing practice of leishmanization which allows rapid evaluation of candidate vaccine(s), it is suggested that a vaccine, at least against L. major, is imminent in the not too distant future.

Animals↗

PubMed1983

Lack of general immunosuppression during visceral Leishmania tropica infection in BALB/c mice: augmented antibody response to thymus-independent antigens and polyclonal activation.

Leishmania tropica causes a lethal visceral disease in highly susceptible BALB/c mice, with many immunopathologic features resembling those in human kala-azar. The responses to thymus-independent antigens of Type 1 and 2 (TI-1, TI-2) were compared in infected mice of susceptible BALB/c and resistant C57BL/6 strains at various times after infection. The infected BALB/c mice had an augmented response to both types of antigens at 45 days after infection. Later (day 76), the response to trinitrophenylated lipopolysaccharide (TNP-LPS, a TI-1 antigen) was diminished but that to dinitrophenylated Ficoll (DNP-Ficoll, a TI-2 antigen) remained statistically above the response of uninfected mice. The response of the resistant strain to either antigen was not modified as a result of the infection. Both strains showed significant polyclonal activation, which was considerably greater in the BALB/c than in the C57BL/6 mice. The observations presented here are in contrast to the widely held belief that a generalized nonspecific immunosuppression occurs in L. tropica infected BALB/c mice.

Animals↗

PubMed1982

Analysis of the antigenic relationship of various derivatives of n-acetyl-muramyl-l-ala-d-isoglutamine (MDP), using anti-MDP antibodies.

Antibodies to N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) were produced in rabbits by injection of MDP conjugated to various carriers [bovine gamma globulin (BGG), methylated BSA or sheep erythrocytes]. The anti-MDP was assayed by a direct enzyme-linked immunosorbent assay (ELISA) using horse radish peroxidase linked to MDP-Lys. Various derivatives of MDP were employed in an inhibition of ELISA for analysis of specificity of antibodies and study of the relationship of configuration to biological activity. The results confirmed previous findings that MDP alone is not immunogenic but can act as a hapten when conjugated to carriers. The antibodies were shown to be primarily directed against the muramyl residue. Modifications of this region of MDP yielded derivatives with weak reactivity against anti-MDP, while some changes of other regions had no effect on its antigenicity. Optical isomers of MDP had reduced activity as compared to MDP and polymeric MDP was a strong inhibitor. The structure and function relationship is discussed for some derivatives.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1982

Visceral Leishmania tropica infection of BALB/c mice: cellular analysis of in vitro unresponsiveness to sheep erythrocytes.

In mice, infection with Leishmania tropica initially produced a nonspecific enhancement of the immune response to sheep erythrocytes as measured both in vitro and in vivo. Subsequently, the spleen cell responses of susceptible mice (BALB/c) to sheep erythrocytes and T- and B-cell mitogens in vitro decreased dramatically, whereas those of the resistant strain (C57BL/6) returned to normal. Analysis of the spleen cells of infected animals revealed that macrophages (the target cells of Leishmania) were not defective. However, both T- and B-cell-depleted splenocyte populations of infected animals lacked the ability to respond in the presence of their corresponding B- and T-cell-depleted populations of normal spleen cells. It was also observed that the addition of various numbers of Leishmania organisms did not alter the response of normal spleen cells in vitro. The results of cocultures of various ratios of cells from the spleen of infected and normal animals ruled out the possibility of a strong active immunosuppression. The decrease of in vitro response is attributed to the depletion of immunocompetent cells in the spleen of infected mice, which is heavily populated by null cells.

Animals↗

PubMed1981

Systemic infection of Leishmania tropica (major) in various strains of mice.

The spleen cells of different strains of mice were cultured and examined for the presence of viable promastigotes one to three months following a cutaneous inoculation of 1 to 2 X 10(6) promastigotes of Leishmania tropica (major). The spleen cultures of all five strains tested (BALB/c, DBA/3, C3H, CBA and C57B1/6) contained organisms. Viable parasites were present in the spleen of resistant strains (C3H, CBA, C57B1/6) even after recovery from their cutaneous lesion. The possible implication of this finding in the long lasting immunity observed in this disease is discussed.

Animals↗

PubMed1981

Studies on visceral Leishmania tropica infection in BALB/c mice. I. Clinical features and cellular changes.

The visceral and lethal infection produced in BALB/c mice by Leishmania tropica (major) is accompanied by splenomegaly, anaemia and reversal of albumin-to-globulin ratio. The percentages of both B and T cells are decreased in the spleen. The spleen and lymph nodes become populated with large Ig-, Thy 1.2- 'null' cells. The similarity of some of these parameters with those produced in human kala-azar is discussed.

Animals↗