2 Rev Iberoam Micol 1997; 14: 2-3 Forum Micológico and fungi: an evolving paradigm with opportunities for the development of new antifungal therapies and vaccines

Arturo Casadevall Departments of (Division of Infectious Diseases) and & of the Albert Einstein College of Medicine, Bronx, New York, USA

The role of immunity in protection with the function of protective antibodies [8]. Hence there against fungal has been uncertain for decades. is now evidence for "good" and "bad" antibodies against This is in sharp contrast to bacteria, viruses, and protozoa fungi. where antibody immunity is widely acknowledged to con- Protection studies with mAbs suggest an explana- tribute to protection. This raises the questions: Do protec- tion for the inconclusive and often contradictory results tive antibodies against fungi exist?; Why has it been so obtained from experiments with polyclonal sera [2]. difficult to demonstrate conclusively that antibody immu- Polyclonal antibody preparations contain antibodies of nity protects against fungi?; Does antibody immunity multiple specificities and isotypes. MAb preparations dif- influence the course of fungal infections? fer from polyclonal antibodv preparations in that they The issue of whether antibody immunity contribu- contain one antibody type of a defined specificity and tes to host defense against fungi is no longer academic. In isotype. The discovery that protective, non-protective and recent years there has been a marked increase in fungal deleterious mAbs exist suggests that the efficacy of poly- infections associated with the HIV epidemic and immuno- clonal antibody preparations reflects their relative propor- suppressive therapies. Systemic mycoses in immunocom- tion of these types of antibodies. In fact, experiments with promised patients are difficult to treat effectively because mAbs in mice have shown that mixing protective and non- antifungal therapy frequently fails to eradicate the infec- protective mAbs reduces the efficacy of the protective tion in the setting of defective immunity. For example, mAbs [8]. Immunization strategies which elicit a predo- C. neoformans infections are usually incurable in AIDS minance of protective antibodies may result in useful anti- patients. In the 1960s Morris Gordon and collaborators body immunity. The experiments with mAbs suggest a established that antibody administration could enhance the new working paradigm for the fungi: the efficacy of anti- efficacy of antifungal [1]. Hence a better body immunity depends on the type of antibody response understanding of the role of antibody immunity may help made [2]. in the design of effective vaccines and/or antibody-based For both C. albicans and C. neoformans epitope therapies. specificity has been demonstrated to be an important Numerous investigators have studied the function determinant of antibody efficacy in protection [4,9]. For of antibody immunity in host defence against fungi [2]. A C. neoformans, antibody isotype has been shown to be a role for antibody immunity in protection against indivi- critical determinant of antibody efficacy: murine IgG3 dual is usually established by correlating the mAbs are not protective but switching from IgG3 to IgGl presence of antibody with protection and/or converted a non-protective mAb into a protective mAb demonstrating protection after passive antibody adminis- [8,10]. This observations suggest that, for some fungi, the tration. Among the medically important fungi, the role of generation of protective antibody responses is dependent antibody immunity has been most extensively studied for on the ability of the host to make antibodies to specific C. albicans and C. neoformans [2]. For both fungi studies epitopes and these antibodies must be of a particular isoty- with polyclonal antibody reagents (i.e. immune sera) have pe. produced conflicting evidence for and against the impor- Specific antibodies may contribute to host defence tance of antibody immunity [2]. Until the mid-1980s all through a variety of mechanisms. For C. neoformans, cap- studies of antibody protection against fungi utilized poly- sule binding antibodies have been shown to be opsonic clonal reagents. In 1987 Dromer et al. [3] demonstrated [11], to enhance killing of yeast cells by macrophages and that a monoclonal antibody (mAb) was protective against microglia [11,12], and to reduce capsular polysaccharide C. neoformans and this observation marks the beginning antigen [2]. Some antibodies to C. albicans may be of new era in the study of antibody function against fungi. directly fungicidal [13]. Antibodies also activate the com- In the past decade, experiments with mAbs have establis- plement system which is important in host defence against hed the existence of protective and non-protective antibo- many fungi [14]. Antibodies may also neutralize fungal dies against C. albicans [4,5] and C. neoformans [3,6,7]. products that contribute to virulence. Furthermore, some mAbs against the C. neoformans cap- The observations that some mAbs protect against sular polysaccharide have been shown to function as bloc- fungi suggest a potential role for antibody immunity in king antibodies that can enhance and interfere host defence against mycotic infections. The discovery that some mAbs to fungal antigens are protective does not challenge the existing view that cell mediated immunity is the main line of defence against fungal infections. Dirección para correspondencia: Protective antibodies may not be made in sufficient quan- Dr. Arturo Casadevall MD, Ph D, Dept of tities to affect the course of infection or their effects may Medicine, Albert Einstein College of Medicine, be counterbalanced by non-protective or blocking antibo- 1300 Morris Park Ave, Bronx, NY 10461.Phone: (718) 430-4260 dies [8]. Nevertheless, the identification of protective anti- E-mail: [email protected] bodies against fungal pathogens is a major development Antibodies and fungi Casadevall A 3 because it raises the hope that vaccines which elicit pro- Given that protective, non-protective and delete- tective antibody immunity can be developed. Such vacci- rious (disease-enhancing or blocking) antibodies exist it is nes could function by eliciting antibody opsonins that possible that the type of antibody response made in res- enhance the function of non-specific (i.e. macrophage, ponse to fungal infection will affect the course of infec- NK cell, neutrophil) and specific (lymphocyte) cell tion. It is striking that only a minority of patients at risk mediated immunity and prevent or help eradicate fungal for invasive fungal infection actually become ill with fun- infections. A polysaccharide-tetanus toxoid conjugate gal infections. For example, only 6-8% of HIV-infected vaccine is being developed [15] which can elicit protecti- patients with CD4 + lymphocytes counts less than 200 ve antibodies in mice. cells/mm3 develop cryptococcosis in [21] Protective antibodies could be potentially useful despite the fact that C. neoformans is ubiquitous in the for the therapy of fungal infections. Antibody administra- environment. Quantitative and qualitative differences in tion was widely used in the pre-antibiotic era for the treat- the serum antibody responses to C. neoformans have been ment of a variety of infectious diseases and antibody described between patients with and without HIV infec- therapy and continues to be used today for some medical tion [22,23]. Thus it is conceivable that derangements in conditions. Antibody-based therapies, if developed, are antibody immunity contribute to the marked susceptibility likely to be used as adjuncts of standard antifungal che- of some populations to fungal infections. motherapy. For C. neoformans, antibodies can enhance In summary, the field of antibody immunity the efficacy of amphotericin B [16,17], fluconazole [18], against fungi is in a renaissance. The application of mono- and 5-flucytosine [13]. Antibody administration can clonal antibody technology to re-examine the role of anti- rapidly clear serum polysaccharide antigen in mice and body immunity has established that antibodies can be humans with cryptococcal infection. Since cryptococcal protective against fungi. The task ahead is to understand antigen has been associated with a variety of deleterious the mechanisms by which antibodies mediate protective effects on host immunity [20] the ability of antibody to effects against fungi and design vaccines which elicit pro- reduce serum antigen could conceivably translate into a tective antibody immunity. therapeutic benefit.

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