Publication Date:
2010-11-19
Description:
Abstract 2542 Graft-versus-host disease (GVHD) and opportunistic infections represent two major causes of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Both of these conditions are respectively mediated or controlled to a large extend by donor-derived T cells. Moreover T cells play a critical role in promoting stem cell engraftment and decreasing the probability of disease relapse. Therefore the separation of the effects of GVHD from the beneficial effects mediated by T cells has been a long-standing challenge of transplantation immunology. The contribution of different subsets of donor T cells to the pathogenesis of GVHD has been studied in different mouse models: both purified naïve CD4+ and CD8+ T cells were able to induce acute GVHD. On the contrary memory T cells failed to induce GVHD. In order to dissect the contribution of different human T cells, we sought to define a xenogeneic model for GVHD in RAG2−/−gc−/− mice. Newborn RAG2−/−gc−/− mice were intraperitoneally (i.p.) injected with either peripheral blood mononucleated cells (PBMC), immunomagnetically selected CD4+ or CD8+ cells, or FACS sorted CD45RA+CD4+ or CD45RO+CD4+ cells. Mice were weaned 3 weeks after birth and were scored weekly for signs of GVHD and bled for human engraftment evaluation. Both PBMC and CD4+ injected groups developed xenogeneic GVHD (x-GVHD) and the survival at 12 weeks was 42% and 53% respectively. The peak of peripheral blood (PB) engraftment was reached between week 6 and 7 and it was about 40% in both groups. Human cells were present in high percentage (〉60%) in the spleen and liver of mice that displayed signs of x-GVHD. Moreover in these mice developed detectable thymi and mesenteric lymph nodes (MLN) which are not normally present in the RAG2−/−gc−/− mice and which were populated by human cells. In PBMC injected mice, CD4+ and CD8+ T cells were the only populations observed with no survival of myeloid, B or NK cells. PBMC or CD4+ groups developed GVHD in 55%, while mice adoptively transferred with CD45RA+CD4+ cells manifested a positive score for x-GVHD (30%) but displayed milder symptoms compared with the PBMC or CD4+ groups. The lesser morbidity and mortality correlated with a lower human engraftment in PB (25% at week 7) and in spleen (about 40%). Only 10% of mice injected with CD45RO+CD4+ cells showed x-GVHD symptoms and the human engraftment level in PB remained below 20%. Finally mice injected with CD8+ cells did not develop any x-GVHD symptoms. The human PB engraftment was low (
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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