RESUMO
Regulatory T (Treg) cells are essential for immune tolerance of embryo implantation, and insufficient Treg cells are implicated in early pregnancy loss. An abortion-prone mouse model was used to evaluate the utility of IL-2 complexed with JES6-1 anti-IL-2 antibody (IL-2/JES6-1) to boost uterine Treg cells and improve reproductive success. IL-2/JES6-1, but not IL-2/IgG control, administered in the periconception phase to CBA/J females mated with DBA/2 males elicited a greater than twofold increase in the proportion of CD4+ T cells expressing forkhead box P3 (FOXP3), and an increase in the ratio of FOXP3+ Treg cells/FOXP3- T conventional cells, in the uterus and its draining lymph nodes at embryo implantation that was sustained into midgestation. An attenuated phenotype was evident in both thymic-derived and peripheral Treg cells with elevated cytotoxic T-lymphocyte antigen-4, CD25, and FOXP3, indicating improved suppressive function, as well as increased proliferative marker Ki-67. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, but this was accompanied by a 6% reduction in late gestation fetal weight, despite comparable placental size and architecture. Similar effects of IL-2/JES6-1 on Treg cells and fetal growth were seen in CBA/J females with healthy pregnancies sired by BALB/c males. These findings show that expanding the uterine Treg cell pool through targeting IL-2 signaling is a strategy worthy of further investigation for mitigating immune-mediated fetal loss.
RESUMO
BACKGROUND: Cryptococcus gattii (Cg) infection emerged in British Columbia in 1999. A longitudinal, clinical description of patients has not been reported. METHODS: Medical records were reviewed for Cg patients identified through surveillance (1999-2007). Risk factors for Cg mortality were explored using multivariate Cox regression; longitudinal patterns in serum cryptococcal antigen (SCrAg) titers and the probability of chest cryptococcomas over time were estimated using cubic B-splines in mixed-effects regression models. RESULTS: Among 152 patients, 111 (73.0%) were culture confirmed. Isolated lung infection was present in 105 (69.1%) patients; 47 (30.9%) had central nervous system infection, with or without lung involvement. Malignancy was the provisional diagnosis in 64 (42.1%) patients. Underlying diseases were present in 91 (59.9%) patients; 23 (15.1%) were immunocompromised, and 23 (15.1%) had asymptomatic disease. There were only 2 (1.8%) culture positive relapses, both within 12 months of follow-up. The estimated median time to resolution of lung cryptococcomas and decline in SCrAg titer to <1:8 was 2.8 and 2.9 years, respectively. Cg-related and all-cause mortality among culture-confirmed cases at 12 months' follow-up was 23.3% and 27.2%, respectively. Cg-related mortality was associated with age >50 years (hazard ratio [HR], 15.6; 95% confidence interval [CI], 1.9-130.5) and immunocompromise (HR, 5.8; CI, 1.5-21.6). All Cg-related mortality occurred among culture-positive cases within 1 year of diagnosis. CONCLUSIONS: Cryptococcomas and serum antigenemia were slow to resolve. However, late onset of failed therapy or relapse was uncommon, suggesting that delayed resolution of these findings does not require prolongation of treatment beyond that recommended by guidelines.