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.
Khalil
E A G
EA
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan. eltahirk@iend.org
Ayed
N B
NB
Musa
A M
AM
Ibrahim
M E
ME
Mukhtar
M M
MM
Zijlstra
E E
EE
Elhassan
I M
IM
Smith
P G
PG
Kieny
P M
PM
Ghalib
H W
HW
Zicker
F
F
Modabber
F
F
Elhassan
A M
AM
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
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D015848:Interleukin-5; D016052:Protozoan Vaccines; D007371:Interferon-gamma