T cells and Cytokines

The role of CD4+ T cells as major players against fungal infections is well established (Lindell et al., 2005; Harmsen & Stankiewicz, 1990; Phair et al., 1990). Depletion of CD4+ T cells results in increased susceptibility to P. pneumonia and other mycotic infections both in mice (Shellito et al., 1990) and rats (Thullen et al., 2003). Differentiation of naive Th into Th1 or Th2 type represents a major determinant of resistance or susceptibility of the host to fungal infections (Shoham & Levitz, 2005). Tipping the balance towards Thl-type responses by the orchestrated effort of IFN-y, IL-6, and IL-12 in the relative absence of IL-4 and IL-10, confers significant protection against different forms of mycoses (Romani, 2002; Hebart et al., 2002; Cenci et al., 1998). A positive lymphoproliferative response characterized by overproduction of IFN-y in cultured cells was noted in healthy individuals receiving cellular extracts of A. fumigatus, or its 88 kDa dipeptidase or the 90 kDa catalase antigens (Hebart et al., 2002). Adoptive transfer of CD4+ splenocytes from mice sensitized against A. fumigatus into naïve mice resulted in prolonged survival following intravenous challenge with viable A. fumigatus conidia (Cenci et al., 2000). The combination of anti-CD40 and IL-2 significantly prolonged the survival of mice infected with C. neoformans (Zhou et al., 2006). This protection was correlated with increased serum concentration of IFN-y and tumor necrosis factor alpha (TNF-a) and decreased fungal burden in kidney and brain tissues, which was found to be dependent on IFN-y as evidenced by lack of protection in IFN-y knockout mice.

The role of CD8+ T cells in protection against infections (fungal and otherwise) is generally dependent upon CD4+ T cell help. CD4 deficiency can impair CD8+ activation or function in nonfungal infections (Ribedly et al., 2000; Wang & Livingstone, 2003). However, recent evidence suggest that generation of fungi-specific effector CD8+ T cells capable of producing protective levels of IFN-y against pulmonary C. neoformans infections is achievable in CD4- mice (Lindell et al., 2005). Neutralization of IFN-y in CD4-CD8+ mice increased macrophage infection by C. neoformans. Depletion of CD4+ T cells in mice did not affect the increased serum concentration of IFN-y induced by anti-CD40 antibody agonist/IL-2 combination treatment (Zhou et al., 2006).

Administration of recombinant human hematopoietic cytokines like granulco-cyte colony stimulating factor (G-CSF), Monocyte-CSF (M-CSF), GM-CSF or IFN-y were reported to shorten the duration of neutropenia (G-CSF and GM-CSF) and enhance the phagocytic and killing activity of neutrophils, monocytes and macrophages (G-CSF, M-CSF and GM-CSF) (Georgopapadakou and Walsh, 1996; Chiou et al., 2000). In cancer patients on corticosteroids, neutropenia predisposes to invasive fungal infections (Ribaud et al., 1999). However, the efficacy of cytokine adjunctive therapy varies depending upon the level/nature of immunosuppression and the antifungal agent used. In A. fumigatus-infected outbred ICR mice pretreated with hydrocortisone, administration of recombinant human G-CSF prior to infection antagonized the action of the azole SCH56592. In these mice, large lung abscesses with polymorphonuclear cells and significant lung burden were evident. Absence of G-CSF in similarly treated mice allowed for effective limitation of the infection characterized by reduced lung fungal burden and longer survival rate (Graybill et al., 1998a). Mice made neutropenic by 5-FC, G-CSF augmented the activity of the azole. In vitro testing of the killing and fungistatic activities of voriconazole versus fluoconazole against C. albicans in the presence of GM-CSF has shown that GM-CSF significantly enhanced the killing by PMNs and the collaboration between PMNs and either of the two azoles to kill C. albicans cells (Vora et al., 1998).

However, given that voriconazole is more potent (>tenfold) anti-Candida azole than fluoconazole, the synergistic effect of GM-CSF was more evident when combined with voriconazole. G-CSF was shown to reverse neutrophil dysfunction against Aspergillus hyphae in HIV-infected nonneutropenic patients (Roilides et al., 1993).

The proinflammatory activity of polyenes (AMB and NY) has been related to their capacity to induce cytokine secretion. AMB is recognized as a pathogen-associated molecular pattern (PAMP) by Toll-like receptor 2 (TLR-2), a pattern recognition receptor (PRR) (Razonable et al., 2005a; Sau et al., 2003). Binding of AMB to TLR-2 on phagocytes causes the release of cytokines only from TLR-2 expressing cells (Sau et al., 2003). Nystatin (NY) mediate its proinflammatory activity through a TLR-1- or TLR-2-induced release of IL-ip, IL-8, and TNF-a (Razonable et al., 2005b). These findings provide new avenues for recruiting cytokine-based modulation of antifungal immunity using drugs that can influence cytokine release.

Cure Your Yeast Infection For Good

Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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