DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance.

Liver interstitial dendritic cells (DC) have been implicated in immune regulation and tolerance induction. We found that the transmembrane immuno-adaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulated conventional liver myeloid (m) DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from C57BL/6(H2(b) ) (B6) WT or DAP12(-/-) mice into WT C3H (H2(k) ) recipients. Donor mDC (H2-K(b+) CD11c(+) ) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte reaction and delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A threefold to fourfold increase in donor-derived DC was detected in spleens of DAP12(-/-) liver recipients compared with those given WT grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, interferon gamma (IFNγ) production by graft-infiltrating CD8(+) T cells and systemic levels of IFNγ were all elevated significantly in DAP12(-/-) liver recipients. DAP12(-/-) grafts also exhibited reduced incidences of CD4(+) Foxp3(+) cells and enhanced CD8(+) T cell IFNγ secretion in response to donor antigen challenge. Unlike WT grafts, DAP12(-/-) livers failed to induce tolerance and were rejected acutely. Thus, DAP12 expression in liver grafts regulates donor mDC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.

[An outbreak of acute pulmonary histoplasmosis among travelers to a bat-inhabited cave in Brazil].

Histoplasmosis is known to be endemic in various parts of the world, especially in North and Latin America. In Japan, Histoplasma capsulatum has rarely been isolated from the natural environment. To date, only seven cases of histoplasmosis have been reported in Japan including some that were contracted in foreign countries. Herein, we report the occurrence of acute histoplasmosis among Japanese travelers who were exposed to bat guano in a cave near Manaus, Brazil. A group of 8 Japanese travelers entered a cave for a total of 2 hours in March, 1993. All the visitors had been healthy and had no history of abnormal chest roentgenograms. From 10 to 20 days after the exposure, 7 (87.5%) of the 8 individuals developed abnormal symptoms including fever, malaise, loss of appetite, myalgia, arthralgia, chest pain and dry cough. Five (62.5%) had nodular infiltrative shadows with or without hilar lymphadenopathy in the chest roentgenograms. Eight (100%) of the individuals showed serologic evidence of histoplasmosis. Despite the small number of subjects, this high rate of infection may be related to the fact that the subjects stayed in an enclosed area where air exchange was minimal, at the end of a deep cave infested with numerous bats. The cave involved has never been documented as being endemic for histoplasmosis. The threat of H. capsulatum infection in bat-inhabited caves should be emphasized to travelers and also to physicians.