A curative immune profile one week after treatment of Indian kala-azar patients predicts success with a short-course liposomal amphotericin B therapy.
BACKGROUND
The present pilot study investigating the minimum dose for short-course single and double-dose treatment of kala-azar with an apparently new liposomal formulation of amphotericin B, Fungisome, led to identification of immunological components for early detection of success and/or failure to cure.


METHODS
Patients were treated with 5, 7.5 (single-dose) and 10 mg/kg body weight (5 mg/kg double-dose) of Fungisome. Immunological investigations involving plasma cytokines and antigen-specific lymphoproliferation and cytokine responses from PBMCs were carried out before, 1 week after Fungisome treatment, at the time of relapse, and again after conventional amphotericin B treatment.


RESULTS
At 1-month follow-up all the patients showed 100% initial cure. However, total doses of 5, 7.5 and 10 mg/kg Fungisome showed 60%, 50% and 90% cure, respectively, at 6-months posttreatment. Patients successfully cured demonstrated downregulation of IL-12 and IL-10 in plasma, and two-fold or more elevation of IFN-gamma, IL-12 and TNF, and significant down-regulation of IL-10 and TGF-beta in culture supernatants 1-week posttreatment irrespective of drug-dose. A differential immune profile, involving insignificant decline in IL-10 and IL-12 in plasma and negligible elevation of IFN-gamma, IL-12 and TNF, and persistence of IL-10, despite decline in TGF-beta in culture supernatants, in apparently cured individuals, corresponded with relapse within 6-months of treatment.


CONCLUSIONS
Immunological investigations revealed significant curative and non-curative immunomodulation 1-week posttreatment, correlating with successful cure and relapse, respectively. Although immune-correlation was dose-independent, almost consistent curative response in patients treated with the highest dose 10 mg/kg reflected a definitive impact of the higher-dose on the immune response. TRIAL REGISTRATION NAME AND NUMBER: Clinical Trials Registry--India (CTRI) CTRI/2009/091/000764.
Mondal
Smriti
S
Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India.
Bhattacharya
Pradyot
P
Rahaman
Mehebubar
M
Ali
Nahid
N
Goswami
Rama Prosad
RP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000666:Amphotericin B / Q000008:administration & dosage*; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult
D000981:Antiprotozoal Agents; D016207:Cytokines; C068538:liposomal amphotericin B; D000666:Amphotericin B