The killer phenomenon in yeasts has been revealed to be a multicentric model for molecular biologists, virologists, phytopathologists, epidemiologists, industrial and medical microbiologists, mycologists, and pharmacologists. The surprisingly widespread occurrence of the killer phenomenon among taxonomically unrelated microorganisms, including prokaryotic and eukaryotic pathogens, has engendered a new interest in its biological significance as well as its theoretical and practical applications. The search for therapeutic opportunities by using yeast killer systems has conceptually opened new avenues for the prevention and control of life-threatening fungal diseases through the idiotypic network that is apparently exploited by the immune system in the course of natural infections. In this review, the biology, ecology, epidemiology, therapeutics, serology, and idiotypy of yeast killer systems are discussed.

IMPORTANCE Acne is a common, multifactorial skin condition, and treatments with novel mechanisms have been elusive. OBJECTIVE To assess the safety and efficacy of clascoterone cream, 1%, a novel topical androgen receptor inhibitor, in 2 phase 3 randomized clinical trials (CB-03-01/25 and CB-03-01/26). DESIGN, SETTING, AND PARTICIPANTS Two identical, multicenter, randomized, vehicle-controlled, double-blind, phase 3 studies conducted from November 2015 to April 2018 evaluated the efficacy and safety of use of clascoterone cream, 1%, in males and nonpregnant females 9 years and older with moderate or severe facial acne as scored on the Investigator's Global Assessment scale. Participants were enrolled if they had 30 to 75 inflammatory lesions and 30 to 100 noninflammatory lesions. INTERVENTIONS Patients were randomized to treatment with clascoterone cream, 1%, or vehicle cream and applied approximately 1 g to the whole face twice daily for 12 weeks. MAIN OUTCOMES AND MEASURES Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear), and a 2-grade or greater improvement from baseline and absolute change from baseline in noninflammatory and inflammatory lesion counts at week 12. Safety measures included adverse event frequency and severity. RESULTS A total of 1440 patients were randomzied in 2 studies. In CB-03-01/25, 353 participants were randomized to treatment with clascoterone cream, 1% (median [range] age, 18.0 [10-58] years; 221 [62.6%] female), and 355 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [9-50] years; 215 (60.6%) female); in CB-03-01/26, 369 participants were randomized to treatment with clascoterone cream, 1% (median [range] age, 18.0 [10-50] years; 243 [65.9%] female), and 363 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [range, 11-42] years; 221 [60.9%] female). At week 12, treatment success rates in CB-03-01/25 and CB-03-01/26 with clascoterone cream, 1%, were 18.4% (point estimate, 2.3; 95% CI, 1.4-3.8; P < .001) and 20.3% (point estimate, 3.7; 95% CI, 2.2-6.3; P < .001) vs 9.0% and 6.5% with vehicle, respectively. At week 12, in both CB-03-01/25 and CB-03-01/26, treatment with clascoterone cream, 1%, resulted in a significant reduction in absolute noninflammatory lesions from baseline to −19.4 (point estimate difference, −6.4; 95% CI, −10.3 to −2.6; P < .001) and −19.4 (point estimate difference, −8.6; 95% CI, −12.3 to −4.9; P < .001) vs −13.0 and −10.8 with vehicle, respectively, as well as a reduction in inflammatory lesions from baseline to −19.3 (point estimate difference, −3.8; 95% CI, −6.4 to −1.3; P < .001) and −20.0 (point estimate difference, −7.4; 95% CI, −9.8 to −5.1; P < .001) vs −15.5 and −12.6 with vehicle, respectively. Adverse events rates were low and mostly mild; the predominant local skin reaction was trace or mild erythema. CONCLUSIONS AND RELEVANCE Use of clascoterone cream, 1%, for acne treatment appears to demonstrate favorable efficacy and...

Single chain fragment (ScFv) antiidiotypic antibodies (antilds) of a killer toxin (KT) from the yeast Pichia anomala have been produced by recombinant DNA methodology from the splenic lymphocytes of mice immunized by idiotypic vaccination with a KT-neutralizing monoclonal antibody (Mab KT4). ScFv KT-like antilds (KTIdAb) react with specific Candida albicans KT cell wall receptors (KTR) exerting a candidacidal activity in vitro could be neutralized by adsorption with Mab KT4. ScFv KTIdAb displayed an effective therapeutic activity in an experimental model of rat candidal vaginitis.

A ssociative recognition is a basic regulatory mechanism of the immune response and refers to the phenomenon in which immunity to one determinant of a multideterminant antigen enhances the response to other determinants. The cooperative effect is mediated by a determinant recognized by T helper cells (Th) and has been demonstrated for B cell responses (T-B cooperation) (1) and cytotoxic T lymphocytes responses (Th-cytotoxic T lymphocyte cooperation) (2). A similar form of associative recognition between two Th cell determinants (Th-Th cooperation) has not been described yet but could prove valuable to responses against poorly immunogenic antigens such as tumor antigens. The immune response against tumor antigens is hindered, among other factors, by down-regulation of MHC molecules, self-tolerance, and functional hierarchy in the immunogenicity of T cell determinants. It is now clear that T cell determinants of protein antigens can be categorized into dominant, subdominant, and cryptic to reflect a different degree of immunogenicity in vivo (3). Consequently, as T cells reactive with dominant determinants of tumor antigens are eliminated in the thymus during negative selection, the adult immune repertoire is composed mainly of precursor cells with moderate avidity for subdominant and cryptic determinants. Thus, methods to heighten the response of CD4 and CD8 T lymphocytes of the residual repertoire against poorly immunogenic determinants are needed to develop better immunogens against cancer.MUC-1, a glycosylated molecule of high molecular weight expressed in malignant tumors of epithelial origin (4, 5), induces both CD8 (6-8) and CD4 T lymphocytes (9, 10) against an antigenic core consisting of a tandem repeat of 20 amino acid residues. For these reasons, MUC-1 is a useful model antigen for targeted manipulations of the immune response. Specific T cell responses against MUC-1 were induced in C57BL͞6 mice using a model of epitope-based genetic vaccination, somatic transgene immunization (11). This approach is based on the inoculation into the spleen of adult mice of plasmid DNA comprising an Ig heavy (H) chain gene controlled by a B cell-specific promoter to target resident B cells (12). The use of Ig genes modified in the complementaritydetermining regions (CDR) to code for heterologous epitopes (13) allows one to direct the in vivo synthesis and secretion by B cells of transgenic Ig, which immunize the host against the B and T cell epitopes expressed in their V region (14,15). Unlike conventional DNA vaccination (16), which induces Th1 responses (17), somatic transgene immunization activates Th0 cells that produce IL-2, IFN-␥, and IL-4 (15). One advantage of somatic transgene immunization is that heterologous epitopes can be assembled on the Ig V region in various assortment and combination to maximize immunogenicity but also to provide easy tools to study the reciprocal regulation between distinct antigenic determinants during the immune response in vivo.Here, we report that an immunologically silent Th cell d...

Rat monoclonal yeast killer toxin (KT)-like immunoglobulin M (IgM) anti-idiotypic antibodies (KT-IdAbs) were produced by idiotypic vaccination with a mouse monoclonal antibody (MAb; MAb KT4) that neutralized a Pichia anomala KT characterized by a wide spectrum of antimicrobial activity. The characteristics of the KT-IdAbs were demonstrated by their capacity to compete with the KT to the idiotype of MAb KT4 and to interact with putative KT cell wall receptors (KTRs) of sensitive Candida albicans cells. The internal-image properties of KT-IdAbs were proven by their killer activity against KT-sensitive yeasts. This lethal effect was abolished by prior adsorption of KT-IdAbs with MAb KT4. These findings stressed the potential importance of antibody-mediated immunoprotection against candidiasis and suggested a feasible experimental approach for producing antimicrobial receptor antibodies without purifying the receptor. KT-IdAbs might represent the basis for producing engineered derivatives with a high potential for effective therapeutic antifungal activity. MATERIALS AND METHODS Strains. P. anomala ATCC 96603 (formerly defined as UP 25F) was used for KT production. P. anomala UM3 and C. albicans UP 10, two yeast isolates known to be sensitive to the activity of the P. anomala KT, were also used in this study. These yeasts were subcultured on Sabouraud dextrose agar plates (Difco Laboratories, Detroit, Mich.) and are maintained in sterile distilled water in our fungus collection. KT production. KT was produced by a previously described procedure (21). Briefly, P. anomala ATCC 96603 was grown for 24 h at 25ЊC in Sabouraud broth (Difco) buffered at pH 4.6 with 0.1 M citric acid and 0.2 M sodium phosphate. The supernatant was filtered and concentrated 50 times with Minicon B15 concentrators (Amicon Division, W. R. Grace & Co., Beverly, Mass.). The concentrated KT was tested for killer activity against a recognized sensitive strain by conventional well assay (33) and was refrigerated (4ЊC) until it was used. Animals. Fischer-344 rats (CPA Rot, Roquemaure, France) were used in this study to produce KT-IdAbs. Immunogen. An immunoglobulin G1 (IgG1) MAb (MAb KT4) which neutralized the activity of P. anomala KT against recognized KT-sensitive strains of C. albicans and which was produced by standard procedures as described previ

T cell immunity is the key to protective immune responses against tumors. Traditionally, this function has been ascribed to CD8 T lymphocytes with cytotoxic activity, which are restricted by MHC class I molecules. In recent years the realization that CD4 T cells can also play a relevant role in protective anti-tumor responses has received growing attention. Here we will discuss the role of MHC class II-restricted T cells in response to, and in the regulation of, tumor antigens. Emphasis will be placed on four areas: (1) the role of CD4 T cell immunity in tumor protection in animal models and putative mode of action, (2) tumor antigens recognized by human CD4 T cells, (3) the cooperation between two CD4 T cells of different specificity as a new way to jump start the response against sub-immunogenic determinants of tumor antigens in a tolerant environment, and (4) the negative impact of regulatory CD4 T cells on anti-tumor T cell responses. By drawing attention to these four areas, it is our intention to provide the reader with a comprehensive view of issues of contemporary importance for this field, in the expectation that the information will help a better design of therapeutic cancer vaccines.

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