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Brahm H. Walsh, Bruce S. Klein, Minoo Battiwalla, Nikolaos G. Almyroudis, Steven M. Opportunistic fungal infections are major causes of morbidity and mortality among immunocompromised individuals. Fungi have evolved complex and coordinated mechanisms to survive in the environment and in the mammalian host. Knowledge of the immunopathogenesis of fungal infections has paved the way to promising strategies for immunotherapy.

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These include strategies that increase phagocyteactivate innate host defense pathways in phagocytes and dendritic cells, and stimulate antigen-specific immunity e. Immunotherapy must be tailored to specific immunocompromised states. Challenges exist in bringing promising immunotherapies from the laboratory to clinical trials. Opportunistic fungal infections are a major cause of morbidity and mortality in immunocompromised patients.

In some patients, the host defense deficit is well defined, such as in patients with chronic granulomatous disease. Others may have multiple defects in immunity. This is particularly the case among recipients of allogeneic hematopoietic stem cell transplants, in whom invasive mold infections have become one of the leading causes of infection-related mortality [ 1—7 ]. Immunotherapy must be tailored to specific immunocompromised states that predispose to opportunistic fungal infections table 1.

We discuss immunotherapies that are currently used in the clinic and novel strategies that are being evaluated in clinical trials and at the preclinical level e. Finally, we outline challenges and pitfalls associated with bringing novel immunotherapeutics to clinical trials. Goals and strategies for augmentation of the immune response to fungal infections.

Colony-stimulating factors CSFs. CSFs are mostly used to accelerate myelopoiesis in Looking 4 fun gal with neutropenia. In a randomized study of patients receiving chemotherapy to treat acute myelogenous leukemia, prophylaxis with granulocyte-macrophage CSF GM-CSF led to a lower frequency of fatal fungal infections than that seen with placebo 1. However, CSF have not produced a survival advantage in other studies. CSFs also augment phagocyte function. G-CSF influences survival, proliferation, and differentiation of all cells in the neutrophil lineage and augments the function of mature neutrophils.

Macrophage CSF increases phagocytosis, chemotaxis, and secondary cytokine production in monocytes and macrophages [ 15 ]. GM-CSF stimulates various neutrophil effector functions and prolongs neutrophil survival in vitro, increases antibody-dependent cytotoxicity of eosinophils, accelerates the proliferation of the monocyte-macrophage system, and is a potent activator of monocytes and macrophages [ 15 ]. Thus, GM-CSF may have a theoretical advantage against pathogens such as Candida and Aspergillus species, for which host defense is dependent on both neutrophil and macrophage function.

A phase II randomized study of G-CSF plus fluconazole for invasive candidiasis and candidemia in nonneutropenic patients showed the safety of G-CSF but was not powered to determine efficacy [ 19 ].

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Currently, the clinical database concerning CSFs as adjunctive therapy for fungal infections is inadequate to assess efficacy. Administration of G-CSF after T cell—depleted, haplotype-mismatched transplantation was associated with faster neutrophil recovery but prolonged cellular immune dysfunction [ 22 ].

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Prospective, randomized trials are required to assess the short-term benefits versus long-term immune consequences of G-CSF in allogeneic hematopoietic stem cell transplantation. Myeloid progenitors. The myeloid progenitors—common myeloid progenitors and granulocyte-monocyte progenitors—have recently been identified. The addition of these progenitors to hematopoietic grafts in mice that had been rendered neutropenic conferred protection against challenge with Pseudomonas aeruginosa and Aspergillus fumigatus [ 23 ].

Novel strategies, such as this approach to accelerate neutrophil recovery, merit further study. Granulocyte transfusions. The rationale for granulocyte transfusions is to provide supportive Looking 4 fun gal for a patient with neutropenia who has a life-threatening infection by augmenting the of circulating neutrophils until neutrophil recovery occurs. Today, the impetus to reevaluate granulocyte transfusions stems largely from improvements made in donor mobilization methods using therapy with G-CSF and corticosteroids [ 24 ].

We reserve granulocyte transfusions for patients with prolonged neutropenia and life-threatening infections refractory to conventional therapy. In allogeneic transplants in which the donor and recipient are seronegative for cytomegalovirus, using cytomegalovirus-seronegative granulocyte donors is advised [ 26 ]. The Transfusion Medicine and Hemostasis Network of the National Heart Lung and Blood Institute is currently in the planning stages of a randomized study of adjunctive granulocyte transfusions among neutropenic patients with severe bacterial and fungal infections.

Granulocyte transfusion in chronic granulomatous disease is supported by the principle that a small of normal phagocytes may be able to complement the oxidative defect in a large of chronic granulomatous disease phagocytes [ 27 ]. Alloimmunization caused by prior therapy with granulocyte transfusions was considered to be a possible mechanism for failure of donor cell engraftment in some patients with chronic granulomatous disease undergoing allogeneic hematopoietic stem cell transplantation [ 28 ].

Several cytokines e. Pappas et al. Netea et al. Invasive molds should be the highest-priority Looking 4 fun gal pathogens on the basis of their associated mortality [ 39 ]. Toll-like receptors TLRs. TLRs are a conserved family of receptors that recognize common protein, carbohydrate, or DNA pattern motifs on microbes, leading to initiation of aling for cytokine production and T cell and dendritic cell maturation.

TLRs recognize motifs on Candida [ 42 ] and Cryptococcus species [ 43 ] and regulate the induced inflammatory responses. TLR4-defective mice are more susceptible to C. In contrast, Aspergillus hyphae, but not conidia, stimulated production of the anti-inflammatory cytokine IL through TLR2-dependent mechanisms.

This switch from proinflammatory to anti-inflammatory als during germination may help Aspergillus to evade host defenses. Wang et al.

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Other investigators found that both TLR2 and TLR4 recognize Aspergillus hyphae, stimulate proinflammatory cytokines in effector cells, and stimulate neutrophil recruitment [ 4647 ]. Local delivery of cytosine guanine CpG oligodeoxynucleotides which al through TLR9 and the Aspergillus allergen Asp f16 resulted in activation of airway dendritic cells capable of inducing Th1 priming and resistance to the fungus [ 48 ].

Recognition of Aspergillus motifs and activation of neutrophils are coordinated by distinct members of the TLR family, each likely activating specialized antifungal effector functions and inflammatory responses [ 50 ].

Indeed, liposomal amphotericin B, in addition to its intrinsic antifungal activity, may stimulate antifungal resistance by activating TLR-4 in neutrophils [ 51 ]. These studies provide a rationale to stimulate or inhibit specific classes of TLRs as a means of enhancing both innate and antigen-specific immunity to fungi. Pentraxins are a superfamily of conserved proteins characterized by a cyclic multimeric structure. Pentraxin 3 is an innate pathogen recognition protein that binds to specific motifs on P. Pentraxin 3—deficient mice were highly susceptible to Aspergillus infection [ 52 ].

These mice demonstrated defective recognition of conidia by alveolar macrophages and dendritic cells, as well as inappropriate induction of type 2 cytokine responses. Administration of pentraxin 3 protected against Aspergillus challenge in murine T cell—depleted allogeneic bone marrow transplant recipients [ 52 ] and potentiated the protective effect of treatment with subtherapeutic levels of amphotericin B [ 53 ]. Antibody-based therapy has seemed promising in a variety of Looking 4 fun gal fungal infections, and pilot clinical trials are underway.

Antibodies directed against capsular epitopes confer protection in murine cryptococcal infection [ 54—58 ]. A murine IgG1 monoclonal antibody 18B7 has shown acceptable safety in a phase I dose-escalating study of patients with treated cryptococcal meningitis [ 59 ]. In addition to functioning as immunomodulators e.

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Mycograb is a human genetically recombinant antibody against the Candida heat shock protein Mycograb conferred protection in cases of murine systemic candidiasis in mice [ 60 ] and is currently being evaluated in clinical trials. Mycograb also demonstrated in vitro synergy with antifungal agents against Aspergillus species [ 61 ] and C. Antibodies targeted against secreted aspartyl proteases and fungicidal anti-idiotypic antibodies with yeast killer toxin activity [ 63 ] have also shown promise in animal models.

Cenci et al. Protective immunity to Candida and Aspergillus species is mediated by antigen-specific Th1 cells. T cells coordinate humoral responses, including antibody class switching. B cell—deficient mice Looking 4 fun gal able to control primary Candida and Aspergillus infection but were unable to control reinfection with C.

Antifungal opsonizing antibodies restored IL production by dendritic cells, a finding suggesting that antibodies may modulate dendritic cell and T cell responses to fungal antigens. Antibody-based therapy has largely been applied to extracellular pathogens.

However, antibodies to a cell surface histone-like protein of H. The effectiveness of antibody-based therapy in experiments involving histoplasmosis is particularly intriguing, because H. Vaccine development is a priority for several fungal pathogens, including C. Many challenges confront vaccine development for fungi, including different host risk factors and modes of fungal pathogenesis.

One impediment to fungal vaccine development is that the patients who are most susceptible to opportunistic fungal infections are those least able to mount protective responses. Wuthrich et al. Another impediment relates to the limited of d vaccine adjuvants. Candidate adjuvants that act on multiple innate and antigen-specific host defense pathways are likely to be the most effective in protecting against opportunistic fungal infections.

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The definition of adjuvants has mostly been restricted to those that stimulated antibody titers e. More recently, the concept of adjuvants has been expanded to include soluble mediators and antigenic carriers e. Heat-shock proteins are an example of naturally produced proteins that have been exploited as vaccine adjuvants in cancer and infectious diseases [ 73—79 ]. Heat-shock proteins exhibit powerful immunostimulatory effects on dendritic cells in a TLR2- and TLR4-dependent fashion [ 8081 ] and induce antibody and type I cellular immunity that may be promising in fungal vaccine development [ 82 ].

Fungi also produce heat-shock proteins that may be targets for vaccine development. Long et al. Immunization with recombinant heat-shock protein 60 from H. Paradoxically, vaccination may be useful to attenuate pathological inflammatory responses or induce tolerance.

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Allergic bronchopulmonary aspergillosis develops from sensitization to airway A. T cells are the key components mediating allergic responses to A. There is ificant interest in immunotherapy for allergic bronchopulmonary aspergillosis, including the use of CpG sequences [ 87 ], recombinant allergens, and peptides to induce tolerance, as well as antigenic and DNA-based vaccines aimed at controlling the Th2-mediated responses in allergic bronchopulmonary aspergillosis [ 88 ].

Adoptive immunotherapy. In mice, the importance of cell-mediated immunity against Aspergillus infection an extracellular pathogen has become well established [ Looking 4 fun gal90 ]. This study also showed the overly simplistic nature of the generalization that host defense against extracellular pathogens e. Cellular adoptive immunotherapy may include not only adoptive transfer of specific Th1 cells but also active vaccination with dendritic cells. Dendritic cells pulsed with C. The infusion of fungus-pulsed dendritic cells accelerated the recovery of functional antifungal Th1 responses in mouse allogeneic hematopoietic stem cell transplant recipients and conferred protection against experimental aspergillosis [ 92 ].

Dendritic cells also have key functions in containing and dampening inflammatory responses by tolerization through the induction of regulatory T cells [ 93 ]. These studies in mice demonstrate that the remarkable functional plasticity of dendritic cells in response to fungi can be exploited for the deliberate targeting of cells and pathways of cell-mediated immunity in response to fungal vaccines in transplantation [ 93—95 ] figure 1.

Illustration of the unique ability of dendritic cells to initiate and control the immune response to fungi. Dendritic cells function at 3 levels in the manipulation of the immune response to these pathogens in mice. First, they mount an immediate or innate response to them e. Second, through pattern recognition receptors e. Third, dendritic cells are important in containing and dampening inflammatory responses by tolerization through the induction of regulatory T Tr cells.

Immunotherapy can be evaluated as preventive or as adjunctive therapy. Prevention should be targeted to patients at ificant risk for the infection of interest and should focus on infections with ificant morbidity or mortality that are inadequately covered by standard therapies.

One challenge relates to accrual of adequate s of patients in trials involving uncommon infections. Assuming a power of 0. This is, in fact, an underestimate, because it does not consider false-positive diagnoses or differences in antifungal prophylaxis and diagnostic evaluation between centers, which would reduce the ability of the analysis to detect a protective effect of vaccination. Selecting a patient population with a higher risk of invasive aspergillosis e.

The paradigm for clinical trial de aimed at preventing infection with dimorphic fungi e. In the s, a randomized placebo-controlled study involving subjects from regions of endemicity showed no benefit of the formalin-killed spherule vaccine in preventing coccidioidomycosis [ 96 ]. Additional candidate vaccines for coccidioidomycosis are being developed [ 97 ].

Studies of adjunctive immunotherapy for established infection should target specific well-defined patient groups to maximize the likelihood of detecting a treatment effect. Kullberg et al. Funding for clinical trials of novel antifungal therapeutics may be the most important hurdle. Vaccines targeted to pathogens that affect a broad segment of the general population have more attractive marketing potential than do vaccines for opportunistic fungal pathogens that affect only those individuals with severe defects in the immune system.

Bringing promising, novel antifungal immunotherapeutics to clinical trials and to market will likely require creative partnerships between academia, industry, Looking 4 fun gal government. Potential conflicts of interest.

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