Clonal dissemination of T-lymphocytes in scid mice from familial hemophagocytic lymphohistiocytosis

Background. Although familial hemophagocytic lymphohistiocytosis (FHL) has been considered a disorder of T-cell dysfunction, there is no evidence of the clonal origin of T-cells in this disease. Procedure. We engrafted mononuclear cells (MNCs) from five FHL patients into scid mice and examined the infiltration of human cells in mouse organs. The characterization of human cells that infiltrated in the mouse organs was then performed. Results. A diffuse infiltration of human lymphoid cells was detected in scid mice treated with 1 x 10(6) MNCs from one of the five patients. These cells were positive for HLA-DR and CD3, but negative for CD4, CD8, CD20, and CD68, suggesting the infiltration of double negative (DN) T-cells. The MNCs from the other four patients induced murine lymphoma-like disease; T-cell lymphoma in one and lymphoma of unknown origin in three. The characterization of these human DN T-cells was performed. The analysis of the V alpha repertoire showed no preferential usage of the vp family in MNCs, while the dominant expression of V beta 13 was detected in T-cells infiltrating in the spleen and lung. A J beta analysis showed the restricted usage of J beta 1.2 for V beta 13 in these cells, and the clonality of V beta 13-J beta 1.2 fragment was confirmed by a single-strand confirmation polymorphism analysis. The analysis of the Va repertoire showed that V alpha 24 was exclusively used in these DN T-cells, but no usage of J alpha Q for V alpha 24 was observed. Conclusions. A clonal expansion of T-cells was induced in scid mice by the engraftment of MNCs from an FHL patient. The infiltration of DN crp T-cells bearing invariant V alpha 24 T-cell receptor in mouse organs may provide a useful clue to the pathogenesis of FHL. In the patients whose MNCs induced murine lymphoma-like disease, some cytokines or unknown factors that stimulate the growth and the tumorigenicity of murine lymphocytes might be produced by the MNCs engrafted in scid mice. Further study is needed to confirm the validity of our experimental approach and the findings observed in scid mice by using more FHL samples. (C) 1999 Wiley-Liss, inc.