title: Dichotomy of protective cellular immune responses to human visceral leishmaniasis.
abstract: 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.
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan. eltahirk@iend.org
authors.forename: E A G
authors.initials: EA
authors.lastname: Khalil
authors.forename: N B
authors.initials: NB
authors.lastname: Ayed
authors.forename: A M
authors.initials: AM
authors.lastname: Musa
authors.forename: M E
authors.initials: ME
authors.lastname: Ibrahim
authors.forename: M M
authors.initials: MM
authors.lastname: Mukhtar
authors.forename: E E
authors.initials: EE
authors.lastname: Zijlstra
authors.forename: I M
authors.initials: IM
authors.lastname: Elhassan
authors.forename: P G
authors.initials: PG
authors.lastname: Smith
authors.forename: P M
authors.initials: PM
authors.lastname: Kieny
authors.forename: H W
authors.initials: HW
authors.lastname: Ghalib
authors.forename: F
authors.initials: F
authors.lastname: Zicker
authors.forename: F
authors.initials: F
authors.lastname: Modabber
authors.forename: A M
authors.initials: AM
authors.lastname: Elhassan
mesh_terms: D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D000953:Antigens, Protozoan / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D007893:Leishmania donovani / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology; D016052:Protozoan Vaccines / Q000276:immunology*; D012882:Skin Tests
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D015848:Interleukin-5; D016052:Protozoan Vaccines; D007371:Interferon-gamma