Distinct Immunity in Patients with Visceral Leishmaniasis from that in Subclinically Infected and Drug‐Cured People: Implications for the Mechanism Underlying Drug Cure

Hailu, Asrat; Menon, Juthika N.; Berhe, Nega; Gedamu, Lashitew; Hassard, Thomas; Kager, P. A.; Olobo, Joseph; Bretscher, Peter A.

doi:10.1086/320994

Cited by 40 publications

(52 citation statements)

References 15 publications

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“…One means is by infecting with 10 6 parasites and partially depleting CD4 T cells close to the time of infection (49), and the other is by infecting susceptible mice with 10 2 parasites rather than with the standard challenge of 10 6 (28). Our proposed mechanism provides an explanation for such means of influencing the Th1/Th2 phenotype of primary and ongoing immune responses (50,51), as decreasing the number of CD4 T cells or lowering the amount of Ag will decrease the Agmediated CD4 T cell interactions needed to generate Th2 cells, and so modulate the response toward a Th1 mode. In contrast, understanding the efficacy of these two maneuvers is problematical in terms of those models in which an activated APC instructs a single CD4 T cell as to the Th1/Th2 phenotype of its progeny.…”

Section: Discussionmentioning

confidence: 94%

“…If the response is efficient in reducing the pathogen load, the effective Ag dose will be reduced, and these circumstances can lead to a stable cell-mediated, Th1 response, required to contain the infection. Therefore, we suggest that modulating the extent of CD4 T cell interactions, by either reducing the Ag load (51) or reducing the number of responding CD4 T cells (50), may be relevant for the treatment of those pathological conditions in which predominant Th1 responses would be effective instead of the ineffective Th1/ Th2 response that develops.…”

Section: Discussionmentioning

confidence: 99%

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The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Rudulier

McKinstry

Al‐Yassin

et al. 2014

The Journal of Immunology

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Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Rudulier

McKinstry

Al‐Yassin

et al. 2014

The Journal of Immunology

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“…Moreover, determining the Th1 or Th2 nature of human immune responses is often problematic. On the other hand, analysis of the relative abundances of pathogen-specific antibodies reveals a distinct pattern of Ig isotypes and IgG subclasses during disease, resistance to treatment, and cure (7,8,17,24). While the types of Igs produced, including different subtypes and subclasses, are regulated by the cytokine environment, elicitation of these immunoglobulins is Leishmania antigen specific.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Immunoglobulin G and Its Subclass Response to Indian Kala-Azar Infection before and after Chemotherapy

Ravindran

Anam

et al. 2004

Infect Immun

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Serologic parameters of kala-azar were evaluated by Western blot analysis. Sera from kala-azar patients with confirmed diagnoses were screened for immunoglobulin G (IgG) and IgG subclass-specific reactivity against Leishmania donovani membrane antigen (LAg). Heterogenous LAg-specific IgG reactivity with numerous proteins with molecular masses ranging from 18 to 190 kDa was observed. Though the individual band patterns were varied, seven polypeptides of approximately 31, 34, 51, 63, 72, 91, and 120 kDa were immunoreactive with all the sera tested from kala-azar patients. The band patterns of the immunoblots of sera from patients after treatment and clinical cure with sodium antimony gluconate revealed a decrease in the frequency of the bands. Still, recognition of the 63-and 120-kDa bands was 100%, and the 55-and 91-kDa fractions were recognized in 93% of the sera from cured individuals. Among the IgG subclasses, IgG1 reacted with the greatest number of polypeptides. The 63-kDa protein was again detected by all of the IgG subclasses of all the sera tested. Other fractions recognized by the subclasses of more than 70% of the serum samples included those of 47, 51, 55, and 78 kDa. Following treatment, 63-and 51-kDa bands were the most reactive with the IgG subclasses. LAg-associated cross-reaction with other reference human antisera revealed a mild reactivity of the 63-kDa polypeptide with some of the serum samples from leprosy, malaria, typhoid, tuberculosis, and healthy controls. Western blot analysis of LAg entrapped in liposomes, strong vaccine candidates against experimental visceral leishmaniasis, revealed a more restricted band pattern. The 63-kDa fraction revealed by all pre-and posttreatment sera showed almost negligible levels of cross-reaction with sera from patients with other diseases or from healthy controls. These observations provide insight into induced immunity during kala-azar infection for future application.Protozoan parasites of the genus Leishmania cause a spectrum of diseases in humans. Cutaneous leishmaniasis is caused by a wide range of species, including Leishmania major and Leishmania tropica in the Old World and Leishmania mexicana, Leishmania braziliensis, and Leishmania amazonensis in the New World. These species cause a form of leishmaniasis characterized by skin lesions rich in parasites, which are usually localized and heal spontaneously. Active visceral leishmaniasis (VL) caused by members of the Leishmania donovani complex, including L. donovani donovani, L. donovani infantum, and L. donovani chagasi, is characterized by fever, cachexia, hepatosplenomegaly, and blood cytopenia and is usually fatal without specific chemotherapy. L. donovani infections in humans, however, do not always result in VL. In areas were VL is endemic, a significant population of individuals has a self-resolving infection detectable only by the development of specific antibodies and/or a T-cell response to leishmanial antigens (18,35,56). Furthermore, patients who have recovered from kala-azar are usually ...

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“…The protective immune mechanisms operating at early stages of skin and liver infection are not well understood. Most subjects recovering from L. donovani infection after drug treatment are protected against repeat infection by Th1-mediated immunity (15). However, one-third of cured patients present subsequent relapses.…”

Section: Introductionmentioning

confidence: 99%

IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

Pitta¹,

Romano²,

Cabantous³

et al. 2009

J. Clin. Invest.

168

206

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Distinct Immunity in Patients with Visceral Leishmaniasis from that in Subclinically Infected and Drug‐Cured People: Implications for the Mechanism Underlying Drug Cure

Cited by 40 publications

References 15 publications

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Characterization of Immunoglobulin G and Its Subclass Response to Indian Kala-Azar Infection before and after Chemotherapy

IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

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