Instead of relying on drugs to reduce the parasite burden of leishmaniasis, and waiting for the effector immune response to develop in time to control the parasites, immunotherapy in conjunction with chemotherapy can rapidly induce the effector immune response. With a safe and potent drug plus an affordable therapeutic vaccine (immunostimulant), which remains to be developed, a single visit by patients with visceral or cutaneous leishmaniasis might be sufficient to induce a quick and lasting recovery. Drug toxicity and the emergence of resistance could also be dramatically reduced compared with present long-term monotherapy. Immunotherapy could be an effective addition to chemotherapy for leishmaniasi

Khalil, E.A.G.

Modabber, Farrokh

Musa, Ahmed Mudawi

Noazin, Sassan

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MIaAabcdaARRAAKLTIIIIpspmvmmaadciii(i0dTransactions of the Royal Society of Tropical Medicine and Hygiene 104 (2010) 1–2Contents lists available at ScienceDirectTransactions of the Royal Society ofTropical Medicine and Hygienejourna l homepage: ht tp : / /www.e lsev ier .com/ locate / t rs tmhini-reviewmmunological stimulation for the treatment of leishmaniasis:modality worthy of serious considerationhmed Mudawi Musaa, Sassan Noazinb, E.A.G. Khalil a, Farrokh Modabbera,c,d,∗Institute of Endemic Diseases, University of Khartoum, Khartoum, SudanWorld Health Organization, 1211 Geneva 27, SwitzerlandLondon School of Hygiene and Tropical Medicine, Keppel Street, London WCIE 7HT, UKDrugs for Neglected Diseases initiative (DNDi) 15 Ch. Louis-Dunant, Geneva 1202, Switzerlandr t i c l e i n f orticle history:eceived 22 February 2009eceived in revised form 21 July 2009ccepted 21 July 2009vailable online 26 August 2009a b s t r a c tInstead of relying on drugs to reduce the parasite burden of leishmaniasis, and waiting forthe effector immune response to develop in time to control the parasites, immunotherapyin conjunction with chemotherapy can rapidly induce the effector immune response.With a safe and potent drug plus an affordable therapeutic vaccine (immunostimulant),which remains to be developed, a single visit by patients with visceral or cutaneouseywords:eishmaniasisherapymmunochemotherapymmunotherapyleishmaniasis might be sufﬁcient to induce a quick and lasting recovery. Drug toxicity andthe emergence of resistance could also be dramatically reduced compared with presentlong-term monotherapy. Immunotherapy could be an effective addition to chemotherapyfor leishmaniasis.© 2009 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. AllmmunocompromisedmmunostimulationLeishmaniasis is caused by the Leishmania genus ofrotozoan parasites, and manifests in various forms:elf-healing or chronic cutaneous leishmaniasis [CL, orost-kala-azar dermal leishmaniasis (PKDL)]; debilitatingucosal leishmaniasis (ML); and fatal (if not treated)isceral leishmaniasis (VL). The natural history of leish-aniasis is depicted in Figure 1 in a simpliﬁed schematicodel applicable to VL and some forms of CL, with thessumption that there is a direct relationship between par-site load and disease. In an immunocompromised host theisease returns upon stopping treatment (Figure 1A). Inured or asymptomatically infected individuals, fulminat-ng disease appears after immunosuppressive drugs or HIVnfection. However, strong immunity is developed follow-ng successful recovery in immunocompetent individualsFigure 1B). Hence the protective immune response is anmportant part of recovery from leishmaniasis.∗ Corresponding author. Tel.: +41 79 815 4318.E-mail address: fmodabber@dndi.org (F. Modabber).035-9203/$ – see front matter © 2009 Royal Society of Tropical Medicine and Hoi:10.1016/j.trstmh.2009.07.026rights reserved.The available treatment options are far from satisfac-tory as they are either expensive (amphotericin B) or toxic(antimonials), or resistant parasites have either emergedor are imminent withmonotherapy (miltefosine and paro-momycin). One solution is to combine these drugs toallow shorter, less toxic and more affordable treatment.This approach is being addressed by WHO, the Drugsfor Neglected Diseases initiative and their endemic coun-try partners. Another approach is immunochemotherapy,whereby a low-dose or short course of an effective drug(possibly one dose of amphotericin B) is given with oneinjection of a vaccine or immunomodulator to quicklyinduce the effector immune response (Figure 1C).Immunotherapy was pioneered and used in thousandsof CL and a few ML patients by Convit et al. in Venezuela.1Machado-Pinto et al. showed a highly signiﬁcant cure ratefor CL using Mayrink’s vaccine (Biobras, Montes Claros,Brazil) plus a low dose of antimonials, with far fewerside effects of myalgia, severe pain at the site of injection,nausea, vomiting, headache, joint pain, etc. than associatedwith full doses of antimonials.2 This vaccine has also beenygiene. Published by Elsevier Ltd. All rights reserved.2 A.M. Musa et al. / Transactions of the Royal Society of TFigure 1. Schematic representation of chemotherapy plus immunother-apy in leishmaniasis. (A) Immunocompromised hosts. Chemotherapyreducesparasite loadand induces short-termcure, but in theabsenceof aneffector immune response, patients ultimately relapse and require main-tenance treatment. (B) Immunocompetent patients. Treatment inducesinitial cure and the host’s immune response maintains parasites undercontrol. Long-lasting immunity is maintained as long as the host remainsimmunocompetent. (C) Immunochemotherapy in immunocompetentpatients or immunocompromised patients with a certain minimumimmunocompetence (after antiviral therapy inHIV-Leishmania coinfectedindividuals). Immunotherapy just after chemotherapy would induce animmune response sooner than inB above, reducing theneed for long-termchemotherapy. This would reduce drug-related toxicity and the emer-gence of resistant parasites. Solid red line: parasite load; broken blue line:effector immune response; small black arrows: duration of chemother-apy. Themore prominent broken blue line in part C indicates the responseinduced by immunotherapy in contrast to that naturally induced by thehost, shown in part B.used in some cases of HIV-Leishmania coinfection in Brazil.Musa et al. used alum-autoclaved L. major plus BCG (RaziInstitute, Iran) in a preliminary trial involving 30 refrac-tory PKDL patients, and showed immunochemotherapyto be superior to chemotherapy (ﬁnal cure rates 100% vs.40%, P<0.004).3 Chronic cases (>6months) are difﬁcultto treat with drugs alone, and are considered to be animportant reservoir of infection. Badaro and colleaguesused a mixture of deﬁned recombinant antigens and anadjuvant (granulocyte-macrophage colony-stimulatingfactor) plus antimony to treat refractory ML patientssuccessfully in a preliminary trial.4 Combining IFN- andantimony were shown to be effective in the treatment ofsome VL and diffuse CL patients in Brazil.5 No vaccine isavailable, but these observations are proof of the principlethat immunostimulation is a valid approach in need offurther investigation, andmay be applicable to most formsof leishmaniasis, including HIV-Leishmania coinfectionunder certain conditions.The mechanism involved is not fully understood. How-ever, in PKDL lesions there is an inﬂux of  T cells, butdiminution of CD1a (Langerhans) cells. It seems that evenin the presence of effector Th1 cells, parasites are not killedand lesions persist. Even IFN- treatment does not cureall patients with leishmaniasis. This may be because ofdown-regulation of B7-1 and up-regulation of B7-2 by IL-10,which leads toapredominantlyTh2 response.6 It shouldbe noted that a minority of PKDL patients attained curewithout showing a pure Th1 response.ropical Medicine and Hygiene 104 (2010) 1–2As vaccination has a long-lasting effect and mostdrugs work quickly, it may be possible to introduceimmunotherapy at the onset of chemotherapy. How-ever, the best time must be studied in different formsof the disease, and in combination with differentdrugs.Immunochemotherapy would have advantages oversecondary chemoprophylaxis (maintenance therapy) forpatients with HIV-Leishmania coinfection, once antiretro-viral treatment had boosted their immune response to acertain level.In all studies except Badaro’s,4 ﬁrst-generation vaccines(FGV; killed promastigotes of different Leishmania spp.)were used. These are inexpensive (less than US$1.0/dose),but they do not meet the current requirements for newvaccines, and except for Venezuela, limited batches wereproduced for trials and they are not available commer-cially. Nevertheless, the experience gained from testingthem in humans has paved the way for novel approachesto treatment. Despite failing to induce adequate prophy-lactic immunity in healthy individuals, FGVs were able toenhance recovery; possibly because, as shown inmice, dif-ferent effectormechanismsmaybe involved inprophylaxis(CD4, Th1) and recovery (CD8).With well-deﬁned second-generation vaccines beingdeveloped, and well-characterized adjuvants now avail-able or being tested for other diseases, notably cancers,immunochemotherapy should be considered as an alterna-tive modality for the treatment of leishmaniasis, includingHIV-Leishmania coinfection, PKDL and chronic refractoryCL, the forms that are difﬁcult to treat with available drugs.Authors’ contributions: AMM, SN, EAGK and FM under-took all the duties of authorship. FM and AMM areguarantors of the paper.Funding: None.Conﬂicts of interest: None declared.Ethical approval: Not required.References1. Convit J, Ulrich M, Zerpa O, Borges R, Aranzazu N, Valera M, et al.Immunotherapy of American cutaneous leishmaniasis in Venezueladuring the period 1990-99. Trans R Soc Trop Med Hyg 2003;97:469–72.2. Machado-Pinto J, Pinto J, da Costa CA, Genaro O, Marques MJ,Modabber F, et al. Immunochemotherapy for cutaneous leishmania-sis: a controlled trial using killed Leishmania (Leishmania) amazonensisvaccine plus antimonial. Int J Dermatol 2002;41:73–8.3. Musa AM, Khalil EAG, Mahgoub FA, Elgawi SH, Modabber F, ElkadaruAE, et al. Immunochemotherapy of persistent post-kala-azar dermalleishmaniasis: a novel approach to treatment. Trans R Soc Trop MedHyg 2008;102:58–63.4. Badaro R, Lobo I, Munos A, Netto EM, Modabber F, Campos-Neto A, etal. Immunotherapy for drug-refractory mucosal leishmaniasis. J InfectDis 2006;194:1151–9.5. Badaro R, Johnson Jr WD. The role of interferon-gamma in the treat-ment of visceral and diffuse cutaneous leishmaniasis. J Infect Dis1993;167(Suppl 1):S13–7.6. Ismail A, Khalil EAG,Musa AM, Elhassan IM, IbrahimME, Theander TG,et al. The pathogenesis of post kala-azar dermal leishmaniasis fromthe ﬁeld to the molecule: does ultraviolet light (UVB) radiation play arole? Med Hypotheses 2006;6:993–9.

Immunological stimulation for the treatment of leishmaniasis: A modality worthy of serious consideration

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