Alloreactive T-cell trafficking after hematopoietic stem cell transplantation

Beilhack A1,3*, Schulz S2,3, Baker J3, Beilhack GF3, Herman EI3, Baker EM3, Landan G3,Nishimura R3, Butcher EC4, Contag CH5 and Negrin RS3.
1Departments of Medicine II, Wurzburg University, Germany
2Department of Pathology, Technical University Munchen, Germany
Departments of 3Medicine, 4Pathology and 5Pediatrics, Stanford University, Stanford, California, USA

Acute graft-versus-host disease (aGVHD) is the major limitation for a broader application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In aGVHD alloreactive donor T-cells attack the recipient’s gastrointestinal tract, liver and skin. To address this unusual tissue tropism we developed luciferase transgenic (luc+) mice and utilized bioluminescence imaging to track adoptively transferred luc+ T-cells non-invasively in living recipients. Either myeloablative conditioned BALB/c (H-2d, 8Gy) or C57Bl/6 (H-2b, 9Gy) recipient mice were transplanted with allogeneic luc+ T-cells (FVB/N, H-2q) and FVB/N wild type bone marrow. We observed that T-cell proliferation was confined to secondary lymphoid organs until day+3 after allo-HSCT. At this time alloreactive T-cells up-regulated specific homing receptors and subsequently migrated via the blood to aGVHD target tissues. When we blocked T-cell entry to specific lymphoid organs we found a high redundancy of these priming sites. However, by preventing T-cell entry to all secondary lymphoid organs aGVHD was completely averted. In subsequent experiments we isolated in vivo primed alloreactive luc+ T-cells from mesenteric lymph nodes, peripheral lymph nodes or the spleen and transferred these cells into conditioned secondary transplantation recipients. Luc+ T-cells attacked aGVHD target tissues irrespective of the original priming site. In contrast, after secondary transfer into non-conditioned recipients luc+ T-cells preferentially homed to lymphoid organs. These data suggests that not the lymphoid priming sites but instead signals from the aGVHD-target tissues dictate the distinct tissue tropism in aGVHD.
A.B. and St. S. contributed equally to this study.