Prophylactic antibiotic treatment exacerbates Graft vs. Host Disease-induced bone marrow failure and spleen hypoplasia

Abstract

Acute graft vs. host disease (aGVHD) is a major complication following hematopoietic stem cell transplantation. Preclinical and clinical studies suggest aGVHD may be potentiated by gut damage and translocation of intestinal microbiota following toxic, pre-transplant conditioning protocols. We recently reported that aGVHD-induced bone marrow (BM) failure and splenic hypoplasia develops in the absence of gut damage suggesting that intestinal bacteria may not be required for disease pathogenesis. Objective Determine whether prophylactic gut decontamination with broad spectrum antibiotics (Abx) affects the onset and/or severity of aGVHD-induced BM and spleen damage. Methods Syngeneic (Bl6) or allogeneic (Balb/c) CD4+CD25−T cells (5×106 cells) were injected into NK cell-depleted Bl6 RAG1−/− recipients. Prior to T cell transfer, RAG1−/− mice received water (ab libitum) containing aspartame (Asp) or an Abx cocktail containing Asp, neomycin and vancomycin for 7 days prior to and following T-cell transfer. Results Treatment of allogeneic mice with Abx reduced colonic bacterial load by more than 20-fold when compared to their Asp-treated counterparts. Abx treatment also resulted in large and significant reductions in BM- and spleen-residing T cells and myeloid cells as well as circulating erythrocytes, platelets and hematocrit when compared to Asp treated mice. These Abx-induced alterations were associated with significant increases (~4-fold) in serum IL-6 levels compared to Asp-treated mice. Conclusions Prophylactic Abx treatment exacerbates aGVHD-induced BM failure and spleen hypoplasia.