Current Molecular Medicine
Volume 5, Number 4, 2005
Contents
Antifungal
Protective Antibodies
Executive
Editor: Luciano Polonelli
Editorial Pp.375-376
Luciano
Polonelli
An Outline of the Role of Anti-Candida
Antibodies Within the Context of Passive Immunization and Protection from
Candidiasis Pp.377-382
A.
Cassone, F. De Bernardis and A. Torososantucci
Defining Criteria for Anti-Mannan Antibodies
to Protect Against Candidiasis
Pp.383-392
J.E.
Cutler
Antifungal and Antitumor Activities of a
Monoclonal Antibody Directed Against a Stress Mannoprotein of Candida
albicans Pp.393-401
M.J.
Omaetxebarria, M.D. Moragues, N. Elguezabal, A. Rodriguez-Alejandre, S. Brena,
J. Schneider, L. Polonelli and J. Ponton
Human Recombinant Antibody to HSP90: A
Natural Partner in Combination Therapy Pp.403-411
R.C.
Matthews and J.P. Burnie
The Cellular Responses Induced by the
Capsular Polysaccharide of Cryptococcus neoformans Differ Depending on
the Presence or Absence of Specific Protective Antibodies Pp.413-420
A.
Vecchiarelli
Insights into Mechanisms of Antibody-Mediated
Immunity from Studies with Cryptococcus neoformans Pp.421-433
A.
Casadevall and L. Pirofski
Protective Antibodies and Endemic Dimorphic
Fungi Pp.435-442
J.D.
Nosanchuk
Protective Antifungal Yeast Killer Toxin-Like
Antibodies Pp.443-452
W.
Magliani, S. Conti, R. Frazzi, L. Ravanetti, D.L. Maffei and L. Polonelli
Abstracts
[Back to top] Editorial
Luciano
Polonelli
In the last few
decades, a plethora of studies have demonstrated the relevance of host acquired
immunity against invasive fungal infections.
The consolidated
consensus that cell-mediated immunity is critical for the successful outcome of
fungal infections has been hampered in recent years by the evidence of the role
that antibodies may play in host immunoprotection against pathogenic fungi.
Today, the major
concern is neither the relative importance of cellular and humoral responses nor
the modalities of functioning and cooperating of the two arms of the immune
system but, rather, the mechanism of action of protective antifungal
antibodies.
In this issue, the
latest and most comprehensive findings on the role played by antibodies in the
antifungal defense are reviewed.
For Candida
albicans, the fungus that has generated the most extensive studies relying
on experimental animal models most mimicking human vaginal candidiasis, the
potential of passive immunization (i.e. immunotherapy) based on antibodies
specific for very characterized virulence factors such as mannans (adhesins),
aspartyl-proteinases, other enzymes, germ tube or molecules critical for
viability such as heat-shock proteins or cell wall b-glucan is addressed by Antonio Cassone and
collaborators.
As a matter of
fact, the mechanism (deposition of complement factor C3 over the entire yeast
cell wall) by which anti-mannan antibodies specific for short chain b-linked oligomannosides as well as a
genetically recombinant antibody against fungal heat-shock protein 90 may be
protective, alone or in combination with conventional antifungal drugs, against
vaginal and disseminated candidiasis is discussed in detail by Jim E. Cutler
and Ruth C. Matthews with James P. Burnie respectively.
According to an
intriguing paradox that existing candidate chemotherapy agents which have
recognized potential to increase the risk of fungus infections may represent an
excellent resource for the discovery of novel antifungals and targets, the
fungicidal and tumoricidal activity of a monoclonal antibody, characterized by
a triple anti-C. albicans activity and directed against a proteinic
epitope of a cell wall stress mannoprotein recognized to be the major target
for secretory IgA, is reported by José Pontón and collaborators.
More general
insights into the mechanisms of antibody-mediated immunity and the dependance
of the cellular response induced by the capsular polysaccharides in the
presence or absence of specific protective antibodies are derived from the
studies of Arturo Casadevall, Liise-anne Pirofski and Anna Vecchiarelli in Cryptococcus
neoformans.
The dimorphic
fungus Histoplasma capsulatum is, moreover, proffered as a prototype for
antibody protection against endemic mycoses by Joshua D. Nosanchuk.
Furthermore, the
potential of human natural, polyclonal, monoclonal and recombinant yeast killer
toxin-like antibodies as well as synthetic killer mimotopes against different
pathogenic fungi (including antibiotic-resistant species and strains) is
proposed as a wide spectrum antifungal therapeutic approach by Luciano
Polonelli’s group.
Overall, this
review summarizes different types of antibodies that can affect the course of
yeast and mould infections through interaction with different cellular targets
such as mannans, heat shock proteins, capsular polysaccharides, surface
proteins, yeast killer toxin receptors which may be envisaged as potential
vaccine candidates on their own.
The paradigm that
the complexity and isotype of protective, non protective and even
disease-enhancing antibodies could account for the uncertainty of their role in
immunity to fungi and the efficacy of antibodies is dependent on the relative
contribution of each of them is now overcome by the technical feasibility and unlimited
availability of reproducible human, humanized monoclonal and single chain
antibodies as well as genetically engineered antibody fragments of defined
specificity which may greatly strengthen the perspectives of antibody-mediated
therapy even in individuals with defective immune responses.
[Back to top] An Outline of the Role of Anti-Candida
Antibodies Within the Context of Passive Immunization and Protection from
Candidiasis
A.
Cassone, F. De Bernardis and A. Torososantucci
The role played by
antibodies (Abs) in the anticandidal defense has long been a matter of
controversy, mostly due to the past inability to clearly define antigen
specificity, the relationship between the type of immune response within the
different settings of experimental and human candidiasis and, last but not
least, a misunderstanding about the role of T helper cell in cell-mediated
versus the humoral immunity. Contributory was also the lack of precise
identification of virulence traits of the fungus which are the best candidates
for a protective Ab response. In recent years, an impressive amount of
experimental evidence, and also some clinical proof, have been generated which
assign to Abs of defined specificity an important role in the anticandidal
defense both at systemic and mucosal sites. Paradigmatic among them, Abs
against defined virulence factors such as adhesins or aspartyl-proteinase
enzymes, or against critical viability molecules such as b-glucan, have been detected or generated
which hold great promise for immunotherapeutic interventions in humans.
[Back to top] Defining Criteria for Anti-Mannan Antibodies
to Protect Against Candidiasis
J.E.
Cutler
Prevention of hematogenously
disseminated candidiasis and mucocutaneous disease, including Candida
vaginitis, through immunological approaches is appealing for the following
reason. A long-acting and safe vaccine that protects against both serotypes of Candida
albicans and other important species, such as C. tropicalis and C.
glabrata, should significantly reduce the incidence of various forms of
candidiasis by these etiologic agents. Through extensive experimentation on
protective responses in experimental animals against Candida mannan
components, others and we have evidence that antibodies specific for
short-chain b-linked oligomannosides are protective
against candidiasis. Although the mechanism of protection against vaginal
infection requires further investigation, experimentally the ability of
antibody to rapidly deposit high amounts of complement factor C3 onto the yeast
cell wall is requisite for enhancing resistance against disseminated
candidiasis.
[Back to top] Antifungal and Antitumor Activities of a
Monoclonal Antibody Directed Against a Stress Mannoprotein of Candida
albicans
M.J.
Omaetxebarria, M.D. Moragues, N. Elguezabal, A. Rodriguez-Alejandre, S. Brena,
J. Schneider, L. Polonelli and J. Ponton
Immunization of
mice with a stress mannoprotein of >200 kDa from the cell wall of Candida
albicans led to the production of monoclonal antibody (Mab) C7. The
immunogen is a major target of secretory IgA and its expression is regulated by
different environmental conditions including temperature, pH, glucose
concentration and ammonium sulphate in the culture medium. Mab C7 reacted with
a peptide epitope present in the >200 kDa antigen as well as in a number of
antigens from the blastoconidium and germ tube cell wall, including enolase. In
addition to its reactivity with C. albicans, Mab C7 also reacted with antigens
present in C. krusei, C, tropicalis, C. glabrata, C.
dubliniensis and C. lusitaniae, as well as in Cryptococcus
neoformans, Scedosporium prolificans and Aspergillus fumigatus.
Mab C7 exhibited four important biological activities, namely inhibition of
adhesion of C. albicans to a variety of surfaces, inhibition of
germination of C. albicans, direct candidacidal activity and direct
tumoricidal activity. In tumor cells, Mab C7 reacted with nucleoporin Nup88, a
reactivity that can be utilized for diagnostic and prognostic purposes.
[Back to top] Human Recombinant Antibody to HSP90: A
Natural Partner in Combination Therapy
R.C. Matthews and J.P. Burnie
Recent years have
seen the development of the concept of combination therapy for treating severe
fungal sepsis. The advantages of this approach are a potential improvement in
patient survival and a reduction in the chance of resistance developing to each
of the single agents. The disadvantage is that combining drugs may increase the
chance of toxicity. MycograbÒ is a
genetically recombinant antibody against fungal heat shock protein 90 (hsp90)
which is poised to become the mainstay of combination therapy. This paper
presents data on how hsp90 is important to fungi and what role it might play in
human disease with possible interactions with interleukin 6 and nitric oxide.
There is discussion of preclinical data demonstrating synergy in vitro
between MycograbÒ and amphotericin
B and caspofungin. The progress of MycograbÒ
through a Phase II pharmacokinetic study when used in escalating doses with a
liposomal amphotericin B preparation has also been reviewed. The concepts
behind a Phase II pivotal study, where MycograbÒ or a placebo was given in combination with a
liposomal amphotericin B drug for five days for the treatment of disseminated
candidiasis are discussed.
[Back to top] The Cellular Responses Induced by the
Capsular Polysaccharide of Cryptococcus neoformans Differ Depending on
the Presence or Absence of Specific Protective Antibodies
A.
Vecchiarelli
The capsule of Cryptococcus
neoformans, the principal virulence factor of this fungus, is composed
primarily of polysaccharide. The predominant component of the polysaccharide
capsule is glucuronoxylomannan (GXM), a compound with potent immunoregulatory
properties. GXM is bound and internalized by natural immune cells affecting
innate and subsequent adaptive immune response. The cellular pattern
recognition receptors involved in GXM binding include toll-like receptor
(TLR)4, CD14, TLR2, CD18, Fc gamma receptor II (FcgRII). This multiple cross-linking leads to a
suppressive outcome that is arrested and even reversed by protective antibodies
to GXM. This review analyzes the immunosuppressive effects induced by capsular
material, considering its pattern recognition receptors, and dissects the
mechanism of monoclonal antibody shifting to immunoactivation.
[Back to top] Insights into Mechanisms of Antibody-Mediated
Immunity from Studies with Cryptococcus neoformans
A.
Casadevall and L. Pirofski
At first glance Cryptococcus
neoformans appears an unlikely microbe to provide a new understanding of
mechanisms of antibody-mediated immunity (AMI), because it is a facultative
intracellular fungal pathogen for which the role of naturally acquired AMI in
host defense is uncertain. However, numerous studies have now established that
certain antibodies (Abs) against C. neoformans are protective in certain
hosts. Studies with Abs to C. neoformans have provided new insights into
AMI and generated new precedents with implications for other pathogens. The
following concepts have emerged: 1) susceptibility to C. neoformans may
be related to qualitative and quantitative aspects of the Ab response; 2)
protective monoclonal Abs can be generated against pathogens even when the role
of humoral immunity is uncertain; 3) Abs to C. neoformans mediate protection
by immunomodulatory effects, thereby linking Ab efficacy to the overall host
immune response; 4) Ab efficacy is critically dependent on fine specificity,
which in turn is affected by immunoglobulin variable region usage, somatic
mutation and constant region usage; 5) the efficacy of passive Ab therapy is a
function of Ab dose and infecting innoculum, with lack of efficacy at the
extremes of Ab concentration; 6) Ab-mediated toxicity resulting from antigen-Ab
complex-induced release of platelet activating factor is isotype dependent.
Observations with C. neoformans have stimulated a reappraisal of the
role of humoral immunity for other pathogens and highlighted the limitations in
current methods of assessing the role of Ab in host defense.
[Back to top] Protective Antibodies and Endemic Dimorphic
Fungi
J.D.
Nosanchuk
The host response
to infection is the outcome of a complex interaction between a microbe and a
host’s innate and adaptive immune system. In this context, the role of antibody
in the endemic mycoses is relatively poorly understood. Recently, a monoclonal
antibody to a cell surface protein has been shown to be protective in a murine
histoplasmosis model. The findings with Histoplasma capsulatum may
provide a paradigm for antibody protection against endemic fungi. This paper
reviews the recent data on protective antibody in histoplasmosis and previous
data supporting a role for antibody in protective responses in other dimorphic
fungi.
[Back to top] Protective Antifungal Yeast Killer Toxin-Like
Antibodies
W.
Magliani, S. Conti, R. Frazzi, L. Ravanetti, D.L. Maffei and L. Polonelli
After several
years of controversy, antibodies (Abs) are now believed to play an important
role in the protection against fungal infections. Among them, recent data are
strongly supporting the relevance of protective yeast killer toxin-like Abs
(“antibiobodies”, KT-Abs), which are able to exert a direct microbicidal
activity by mimicking a killer toxin (PaKT) and its interaction with
cell wall receptors on susceptible cells essentially constituted by b-glucans. This review will focus on the
implications of the yeast killer phenomenon, and, particularly, the occurrence
and antimicrobial activity of protective antifungal KT-Abs, such as those
produced during the course of experimental and natural infections caused by PaKT-sensitive
microorganisms or produced by idiotypic vaccination with a PaKT-neutralizing
mAb. The strong therapeutic activity exerted against different experimental
mucosal and systemic mycoses by monoclonal and recombinant microbicidal KT-Abs
(either in their soluble forms or expressed on human commensal bacteria) as
well as by a synthetic killer peptide (KP, an antibody fragment engineered from
the sequence of a recombinant KT-Ab) will be discussed. The surprisingly wide
antimicrobial spectrum of activity against eukaryotic and prokaryotic
pathogenic agents, such as fungi, bacteria and protozoa, of these Abs and Ab-derived
molecules suggests new potential strategies for transdisease anti-infective
prevention and therapy.