Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments

Abstract

The IgM mAbs 12A1 and 13F1 are protective and nonprotective, respectively, against lethal Cryptococcus neoformans infection in mice. To better understand the variables that contribute to IgM efficacy against C. neoformans, we studied the effects of inoculum size, route of infection, and Ab dose for each of these mAbs. mAb 13F1 did not prolong survival under any condition studied. mAb 12A1 prolonged survival after the administration of certain Ab doses after i.p. infection with defined inocula and promoted phagocytosis, agglutination, and the formation of inflammatory cell rings around yeast cells in vivo. Large Ab doses of mAb 12A1 resulted in either no protection or enhanced infection, consistent with a prozone-like effect. Investigation of this phenomenon revealed that the fungal cell was protected against microbicidal nitrogen-derived oxidants when large amounts of Ab were bound to the C. neoformans capsule. mAb 12A1 was opsonic in vitro for peritoneal, but not splenic or alveolar macrophages. In summary, our results indicate that IgM efficacy against C. neoformans is a function of the route of infection, inoculum, and Ab dose and is associated with its ability to promote opsonization, agglutination, and phagocytic ring formation in vivo. The occurrence of the prozone-like phenomenon implies that high Ab titers are not necessarily beneficial in assuring protection against certain pathogens and that caution should be exercised in using high Ab titer as a measure for vaccine efficacy.

Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum

“…Phagocytosis of Hc opsonized with protective mAb was greatest with CHO cells transfected with CR3, and the phagocytic index was significantly greater than that from these cells incubated with yeast and control mAb (P < 0.001). The phagocytic indexes were lower with CHO cells, consistent with prior findings that the ingestion process in these cells is not as efficient as for murine macrophages (28). In summary, the protective mAb 9C7 promoted phagocytosis of Hc through CR3 in a complement-independent process.…”

“…The delay in growth of Hc in the presence of cell wall-binding mAb may be due to direct interference with the biosynthesis and organization of the cell wall, which is a mechanism proposed for mAb's to cell wall constituents in C. neoformans (59,60). The finding that IgM promoted phagocytosis through CR3 independently of complement is reminiscent of a recent report that specific IgM to C. neoformans promoted phagocytosis of that fungus by facilitating complement-independent polysaccharide-CR3 interactions (28).…”

“…Although the administration of Hc-binding mAb prior to infection significantly increases survival of lethally infected mice, the efficiency of IgM-mediated phagocytosis must be interpreted in the context of the lung's limitations with respect to IgM function (28,45). Lung macrophages express low levels of CR3, which our work shows is the opsonic receptor for Hc IgM-mediated phagocytosis.…”

Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

“…Longer-lived isotopes such as yttrium-90 (t 1͞2 ϭ 2.7 d), lutetium-117 (t 1͞2 ϭ 6.7 d), or Iodine-131 (t 1͞2 ϭ 8 d) can be used for treatment of infection within abscesses or in the difficult-to-access sites deep in the body. Another advantage of RIT relative to naked antibody therapy is that the latter can be complicated by the occurrence of prozone-like effects at high-antibody concentrations (47). Because the killing power of RIT is based on radiation, and the amounts of antibody administered are low, prozone-like phenomena are not expected to occur.…”

Avaliação do peptídeo sintético (P10): associado ao tratamento quimioterápico em camundongos BALB/c anérgicos infectados com Paracoccidioides brasiliensis.

“…Other phagocytosis experiments were carried out with the J774.16 macrophage-like cell line, derived from a reticulum cell sarcoma (37), or with the MH-S line, originated from an SV40-transformed adherent cell-enriched population of alveolar macrophages (23). The protocol for in vitro phagocytosis was that described in earlier studies (46,47) with minor modifications. Primary cells were plated on 96-well tissue culture plates (Switzerland) at a final density of 1.6 ϫ 10 5 cells/well, and macrophage-like cells were plated at a density of 0.8 ϫ 10 5 to 1 ϫ 10 5 macrophages in order to obtain the same density after overnight incubation.…”