Antibody response to Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan in patients after solid-organ transplantation

Abstract

Cryptococcosis is an important complication of solid-organ transplantation, but the risk factors for disease are poorly understood. The goal of this study was to investigate whether specific or nonspecific serum immunoglobulin levels determined in samples obtained before and after solid-organ transplantation differed in patients who did or did not develop cryptococcosis after transplantation. We analyzed pretransplantation sera from 25 subjects, 15 who subsequently developed cryptococcosis and 10 who did not, and posttransplantation sera from 24 subjects, 13 who developed cryptococcosis and 11 who did not. All subjects received a tacrolimus-based immunosuppressive regimen. Total immunoglobulin levels were measured by immunodiffusion, and Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM)-specific serum antibody levels were determined by enzyme-linked immunosorbent assays. The results showed that solid-organ transplantation had a significant effect on total immunoglobulin and GXM-reactive antibody levels. GXM-reactive antibody levels differed in subjects who did and did not develop cryptococcosis. In pretransplant serum samples, the levels of GXM-reactive immunoglobulin M (IgM) were significantly lower in subjects who developed cryptococcosis after transplantation than in those who did not. For posttransplant serum samples, the levels of GXM-reactive IgM and IgG were significantly higher among the subjects who developed cryptococcosis than among those who did not. These findings suggest that perturbations in the preexisting antibody or B-cell repertoire and/or related to treatment of rejection, transplantation, or immunosuppressive therapy could translate into an increased risk for transplant-associated cryptococcosis.

FIG. 1.

Total immunoglobulin concentrations in pre- and posttransplant serum samples from solid-organ transplant recipients. Scatterplots of concentrations of IgM, IgG, and IgA for subjects before (Pre) and after (Post) the transplant are shown. Each point shows the value for one individual, and the median values are indicated by black bars. All comparisons were made by the Mann-Whitney U test. The asterisk indicated that the values were significantly different (P < 0.0001) for IgA levels in pretransplant samples compared to those in posttransplant samples.

FIG. 2.

Levels of IgM and IgG to GXM in sera of solid-organ transplant recipients. Scatterplots of inverse titers of IgM and IgG to GXM in sera from subjects who developed cryptococcosis (CN+) or who did not develop cryptococcosis (CN−) in samples obtained pretransplantation (A) and posttransplantation (B). Each point shows the value for one individual, and the median values are indicated by black bars. In panel A, the asterisk indicates that the values for IgM to GXM in subjects who or did not develop cryptococcosis in pretransplant samples were significantly different (P = 0.0003). In panel B, the asterisk indicates that the values for GXM-specific IgM and IgG in subjects who or did not develop cryptococcosis in posttransplant samples were significantly different (P < 0.003).

FIG. 3.

Effect of transplantation on IgM to GXM. The levels of IgM to GXM in paired serum samples from nine C. neoformans-positive subjects before transplantation (Pre-Tx) and after transplantation (Post-Tx) are shown.

FIG. 4.

Levels of antibody to PPS in sera from solid-organ transplant recipients. Scatterplots of inverse titers of IgM and IgG to PPS in pretransplant (A) and posttransplant (B) samples from subjects who developed cryptococcosis (CN+) or who did not develop cryptococcosis (CN−) are shown. Each point shows the value for one individual, and the median values are indicated by black bars. The asterisk indicates that the level of IgM was significantly higher in pretransplant samples in subjects who did not develop cryptococcosis than in subjects who developed cryptococcosis (P < 0.04).

FIG. 5.

Levels of antibody to TT in sera from solid-organ transplant recipients. Scatterplots of inverse titers of IgM and IgG to TT in pretransplant (A) and posttransplant (B) samples from subjects who developed cryptococcosis (CN+) or who did not develop cryptococcosis (CN−). Each point shows the value for one individual, and the median values are indicated by black bars. The asterisk indicates that the level of IgG in posttransplant samples was significantly higher (P < 0.03) in subjects who developed cryptococcosis than in subjects who did not develop cryptococcosis.