Elsevier

Blood Cells, Molecules, and Diseases

Volume 33, Issue 3, November–December 2004, Pages 248-255
Blood Cells, Molecules, and Diseases

Prospects for dendritic cell vaccination against fungal infections in hematopoietic transplantation

https://doi.org/10.1016/j.bcmd.2004.08.011Get rights and content

Abstract

Dendritic cells (DCs) are uniquely able to initiate and control the immune response to fungi. DCs function at three levels in the manipulation of the immune response to these pathogens. First, they mount an immediate or innate response to them, for example, by producing inflammatory mediators upon capture and phagocytosis; second, through these preceding innate functions, they decode the fungus-associated information and translate it in qualitatively different Th responses, and third, they are key in containing and dampening inflammatory responses by tolerization through the induction of regulatory T cells (Treg). DCs sense fungi in a morphotype-specific manner, through the engagement of distinct recognition receptors ultimately affecting cytokine production and costimulation. Both myeloid and plasmacytoid murine and human DCs phagocytose fungi and undergo functional maturation in response to them. However, their activation program for cytokine production was different, being IL-12 mainly produced by myeloid DCs and IL-12, IL-10 and IFN-α mainly produced by plasmacytoid DCs. This resulted in a distinct ability for T cell priming, being Th1, Th2, and Treg differently activated by the different DC subsets. The ability of fungus-pulsed DCs to prime for Th1 and Th2 cell activation upon adoptive transfer in vivo correlated with the occurrence of resistance and susceptibility to the infections, respectively. Antifungal protective immunity was also induced upon adoptive transfer of DCs transfected with fungal RNA. The efficacy was restricted to DCs transfected with RNA from yeasts or conidia but not with RNA from fungal hyphae. The effect was fungus-specific, as no cross-protection was observed upon adoptive transfer of DCs pulsed with either fungal species. The infusion of fungus-pulsed or RNA-transfected DCs accelerated the recovery of functional antifungal Th1 responses in mice with allogeneic hematopoietic stem cell transplantation (HSCT) and affected the outcome of the infections. As the ability of phagocytose fungi was defective in peripheral DCs from patients with HSCT, soon after the transplant, our findings suggest that the adoptive transfer of DCs may restore immunocompetence in HSCT by contributing to the educational program of T cells. Thus, the remarkable functional plasticity of DCs in response to fungi can be exploited for the deliberate targeting of cells and pathways of cell-mediated immunity in response to fungal vaccines.

Introduction

In the past decades, the frequency of opportunistic fungal infections has increased, and the spectrum of fungal pathogens has changed [1]. The increasing number of susceptible hosts, the introduction of newer modalities for hematopoietic stem cell transplantation (HSCT), the evolution of organ transplantation practices, the use of novel immunosuppressive agents, and current antimicrobial prophylactic strategies have likely contributed to the changing epidemiology of invasive mycoses. The trends in time of onset, spectrum, and frequency of infections due to invasive molds and opportunistic yeasts are unique for different fungi and vary between subsets of immunocompromised hosts [1]. Opportunistic fungal pathogens, which more typically require immunosuppression to infect the host, include Candida albicans, which is a normal inhabitant of the human gut, and Aspergillus fumigatus, which is ubiquitous in the environment [2], [3]. As a pathogen, C. albicans is associated with a wide spectrum of diseases in humans, ranging from allergy, severe intractable mucocutaneous diseases to life-threatening bloodstream infections [2]. Aspergilli are respiratory pathogens, and pulmonary infections are usually acquired through the inhalation of conidia able to reach small airways and the alveolar space, where the impaired host defense mechanisms allow hyphal germination and subsequent tissue invasion. A. fumigatus is associated with a wide spectrum of diseases ranging from benign colonization of the lung and allergy to life-threatening diseases such as invasive pulmonary aspergillosis or allergic bronchopulmonary aspergillosis [3]. Aspergillus species are the most common cause of invasive infections in allogeneic HSCT [3]. Prophylactic antifungal therapy had little effect on disease incidence in these patients [4].

Section snippets

Immunity to fungi

Host defense mechanisms against fungi are numerous and range from relatively primitive and constitutively expressed nonspecific defenses to sophisticated adaptive mechanisms that are specifically induced during infection [5]. Although the role of innate immunity was originally considered to be a process for defense of the host early in infection, it is now clear that there is an important reciprocal relationship between innate and adaptive immune responses. Through the involvement of a set of

DCs as natural adjuvants

Since their original discovery in 1973, DCs have assumed center stage as the key initiator of adaptive immunity [12]. In infections, they are central in the balancing act between immunopathology and protective immunity generated by host–microbe interactions. DCs are strategically located at the interface of potential pathogen entry sites and take up antigen, move into secondary lymphoid tissues, and activate both helper and cytotoxic T cells. Pathogen-mediated activation induces DCs to undergo

In vitro

Efficient responses to the different forms of fungi require different mechanisms of immunity [5]. DCs showed a remarkable functional plasticity in response to the different forms of fungi, being able to discriminate between the different forms in terms of maturation, cytokine production, and induction of Th cell reactivity, in vitro and in vivo [15], [16]. Murine and human DCs, of both myeloid (MDCs) and plasmacytoid (PDCs) subsets, were able to phagocytose Candida yeasts, Aspergillus conidia,

DCs translate fungus-associated information to Th1, Th2, and Treg cells

Upon exposure to Candida or Aspergillus, DCs activated different types of naive CD4+ Th cells in vitro and in vivo [15]. In vitro, CD4+ T murine splenocytes cocultured with yeast- or conidia-pulsed DCs produced high levels of IFN-γ, but not IL-4 or IL-10. In contrast, DCs exposed to hyphae induced low levels of IFN-γ, but high levels of IL-4 and IL-10 [21]. Adoptive transfer in vivo of purified DCs pulsed with yeasts/conidia or hyphae resulted in priming of CD4+ T cells for Th1 or Th2 cytokine

Exploiting DCs as fungal vaccines in hematopoietic transplantation

Fungus-pulsed DCs activated CD4+ Th cell responses upon adoptive transfer into immunocompetent mice [17], [19], [21]. Previous work has demonstrated the dependency of the efficacy of DC delivery in vivo on the subcutaneous route of administration [17]. We found that DCs delivered subcutaneously migrated to the lungs, spleen, thoracic lymph nodes, Peyer patches, and interestingly, thymus of mice, as indicated by the presence of CFSE-labeled cells in these organs. The ability of DCs to migrate to

Conclusions and perspectives

A variety of cytokines, including chemokines and growth factors, proved to be beneficial in experimental and clinical fungal infections [47]. However, establishing the clinical utility of cytokines as therapy for fungal infections in patients has been difficult. The Th1/Th2 balance itself was also found to be the target of immunotherapy. Thus, the deliberate targeting of cells and pathways of cell-mediated immunity to the fungus may represent a useful strategy in developing effective strategies

Acknowledgments

We thank Dr. Lara Bellocchio for superb editorial assistance. This study was supported by the National Research Project on AIDS, contract 50D.27 “Opportunistic Infections and Tuberculosis,” Italy.

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    This paper is based upon a presentation at a Focused Workshop on Haploidentical Stem Cell Transplantation sponsored by The Leukemia and Lymphoma Society held in Naples, Italy, from July 8 to 10, 2004.

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