A human skin explant model for predicting graft-versus-host disease following bone marrow transplantation.

Abstract

Graft-versus-host disease (GVHD) is the most serious complication following bone marrow transplantation, with an incidence of 40-60%. The disease can be fatal in 50% of cases, even in patients receiving marrow from an HLA identical sibling. Several assays have been developed to try to predict the development of GVHD, including mixed lymphocyte culture reaction, cytotoxic T lymphocyte precursor, and helper T lymphocyte precursor frequency assays. This review describes an in vitro skin explant model which has been used since 1988 for both predicting acute GVHD in HLA identical sibling bone marrow transplantation and studying the pathophysiology of the disease. The model involves sensitising donor lymphocytes in vitro in a primary mixed lymphocyte reaction and then evaluating the secondary response on patient skin biopsies by grading the graft-versus-host reactivity (grades I-IV) histopathologically. From analysis of collective data the model is a clear predictor of GVHD and superior to the other assays widely used, with a correlation of 82% with clinical outcome. The skin explant model allows the investigator to study the pathogenesis of GVHD. The cytokines TNF and IFN are shown to be important mediators of cellular damage in graft-versus-host reactions. Recent work has also involved using the model to study the alloreactivity of cord blood. The model is currently being assessed in several bone marrow transplantation centres in Europe on diVerent patient groups including those who receive marrow from haploidentical and matched unrelated donors. (J Clin Pathol 1999;52:910-913)

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

“…It was prospectively tested as a method to predict GvHD incidence and severity in a donor/patient cohort by Vogelsang et al (1985). Several studies used the skin explant assay to predict the likelihood of acquiring GvHD and reported correlation rates of 80–90% with clinical outcome, which proved the skin explant assay superior to other in vitro models that had been designed for this purpose (Sviland and Dickinson, 1999; Dickinson et al, 2001; Hromadnikova et al, 2001; Sviland et al, 2001; Wang et al, 2006). The accuracy of the prediction by skin explant, however, was dependent on the type of GvHD prophylaxis and conditioning regimens used.…”

“…The skin explant closely resembles the histopathology of cutaneous GvHD and allows the study of pathophysiological processes related to GvHR (Sviland and Dickinson, 1999; Dickinson et al, 2001; Dickinson et al, 2002). Histological grading of the skin explant, from grade I to grade IV with increasing severity (Lerner et al, 1974), represents a standardized method to evaluate the risk for selected donor/recipient combinations before transplantation.…”

“…Briefly, lymphocytes from the spleens of donors are stimulated with irradiated lymphocytes from the spleens of recipients in a mixed lymphocyte reaction for 7 days, then transferred to a cultured skin biopsy of the recipient and co-incubated for three more days. The GvHR is then evaluated and scored by histology using the same criteria as for grading GvHR in human skin explants (Sviland and Dickinson, 1999). Using genetically well-defined inbred strains, we showed that combinations with differences in major histocompatibility antigens usually led to grade III or IV GvHR (Novota et al, 2008).…”

Skin biopsies for early diagnosis and prognosis of graft-versus-host disease in recipients of allogeneic stem cells from blood or bone marrow

“…[14][15][16][17][18][19][20] These studies indicate that skin biopsies have been of limited value to confirm or predict the development of systemic GVHD that requires steroid treatment. Our main objective was to investigate with histopathological and immunohistochemical methods whether the source of stem cells might influence the development of GVHD, and thus possibly acquire new insight into the mechanisms involved.…”

Acute graft-versus-host disease

“…Studies in mice have shown that host antigen-presenting cells, in particular dendritic cells, are essential, 15 and the cytokines released by tissue damage upregulate MHC gene products on those cells. 16 One test used skin biopsies from the patient in a co-culture system with lymphocytes from the prospective donor. Minor histocompatibility antigens (miHA) are also presented by MHC molecules.…”