Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease.

One of the principal target organs during graft-versus-host disease (GvHD) is the intestinal epithelium, although the reasons for the preferential involvement of particular organs in this disease are not known. This study analyzed the subset distribution of donor and host lymphocytes in the small intestinal epithelium and the spleen during GvHD in a parent (C57BL/6J) into F1 (C57BL/6JxDBA2/J F1) model. While the donor cell population in the spleen consisted of B and T cells, the donor cell population in the intestine contained only T cells during the course of GvHD. These infiltrating donor cells resembled the host intraepithelial lymphocytes (IELs), which are predominantly CD8+ T cells. This subset distribution of donor cells in the intestinal epithelium was remarkable since they originated from a donor splenocyte population containing few CD8+ lymphocytes. In addition, although the injected donor splenic T cells were virtually all alpha/beta TCR+, several months after GvHD induction more than 30% of the donor cells in the intestine were gamma/delta TCR+, thereby resembling the host IELs not only in their expression of CD4 and CD8, but also in their TCR expression. In contrast, no gamma/delta TCR+ donor cells were detectable in the spleen of GvHD mice. The subset distribution of donor and host IELs remained constant throughout the disease, while in the spleen a decrease of both donor and host B cells and a temporary increase of both donor and host CD8+ cells was observed. These findings demonstrate that in a given target organ during GvHD the disease process affects both donor and host lymphoid populations. In addition the different tissue microenvironments eventually lead to donor cell repopulation with a subset distribution similar to the host natural lymphoid population of the particular target organ.

Bystander injury of host lymphoid tissue during murine graft-verus-host disease is mediated by nitric oxide.

The suppressed lymphocyte proliferative responses characteristic of graft-versus-host disease (GVHD) are due, in part, to production of nitric oxide (NO). In order to more fully elucidate the role of NO during GVHD, an NO synthesis inhibitor, aminoguanidine (AG), was administered to unirradiated (C57BL/6J X DBA/2J)F1 mice injected with 5 X 10(7) C57BL/6J splenocytes. Administration of AG resulTed in abrogation of the elevation in serum NO2- + NO3- levels characteristic of GVHD. A significantly increased percentage of splenocytes of host phenotype (H2b/d, B220+, and THY1.2+) and a significantly higher hematocrit value were detected in GVHD animals receiving AG therapy. Additionally, the Con A-induced proliferative response of splenocytes obtained from GVHD mice receiving AG therapy was increased compared with the responses of splenocytes from animals that did not receive AG therapy. Parameters not affected by AG therapy included NO synthesis by recovered peritoneal macrophages, donor antihost cytolytic activity in splenocyte populations, serum GM-CSF levels and long-term engraftment of donor cells. These data indicate that NO may play a role in the destruction of both lymphoid and erythroid host tissue as well as the reduced lymphoproliferative responses associated with the acute phase of GVHD.