Cytokine responses and progression to active tuberculosis in HIV-1-infected Ugandans: a prospective study

Elliott, Alison M.; Hodsdon, Wendy; Kyosiimire, Jacqueline; Quigley, Maria A.; Nakiyingi, Jessica; Namujju, Proscovia B.; Watera, Christine; French, Neil; Gilks, Charles F.; Dockrell, Hazel M.; Whitworth, James

doi:10.1016/j.trstmh.2004.01.007

Cited by 25 publications

(19 citation statements)

References 29 publications

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“…12,26 In addition, an association between systemic IL-5 and progression to active TB was found in a study involving more than 600 human immunodeficiency virus-negative Ugandan adults with the trend being most pronounced in the group of BCG-vaccinated individuals. 27 This was interpreted as the existence of a Th2 bias at the time of vaccination resulting in increased susceptibility to TB. Although at present no experimental data support the hypothesis, it may have significant relevance for vaccine design and development.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection

et al. 2008

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SummaryIt is known that protection against tuberculosis is mediated primarily by T helper type 1 (Th1) cells but the influence of the Th1/Th2 balance of a vaccination response on the subsequent protection and pathology during infection has not been studied in detail. We designed a panel of Ag85B-ESAT-6 subunit vaccines based on adjuvants with different Th1/Th2-promoting activities and studied cellular responses, bacterial replication and pathology in the lungs of mice infected with Mycobacterium tuberculosis. All vaccines induced cell-mediated and humoral responses but with markedly different interferon-c : interleukin-5 (IFN-c : IL-5) and immunoglobulin G1 (IgG1) : IgG2 ratios. The vaccines promoted different levels of control of bacterial replication with the most efficient protection being exerted by cationic liposomes containing monophosphoryl lipid A and low to completely absent immunity with conventional aluminium. The level of protection correlated with the amount of IFN-c produced in response to the vaccine whereas there was no inverse correlation with the level of IL-5. Characterizing a protective response was an accelerated recruitment of IL-17 and IFN-c-producing lymphocytes resulting in the early formation of granulomas containing clustered inducible nitric oxide synthase-activated macrophages. In comparison, non-protected mice exhibited a different inflammatory infiltrate rich in neutrophil granulocytes. This study indicates that the adjuvant component of a tuberculosis vaccine may be crucial in determining the kinetics by which effective granulomas, pivotal in controlling bacterial growth, are formed.

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Section: Discussionmentioning

confidence: 99%

Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection

et al. 2008

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“…Treg cell function was not investigated in either study (94,138). Interleukin-10 (IL-10) can suppress IFN-␥ production and DTH responses to mycobacterial antigens (10,37,44). Thus, TB-IRD may be a consequence of ART restoring a CD4 T-cell response to mycobacterial antigens that results in a relative deficiency of IL-10 or other regulatory cytokines compared with IFN-␥.…”

Section: Introductionmentioning

confidence: 99%

Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

et al. 2009

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SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

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“…CD4 T cells are critical, because impairment of CD4 responses, as seen in HIV infection, leads to increased susceptibility to TB (11). CD8 T cells may also be important for protection (12)(13)(14)(15).…”

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confidence: 99%