Host and Donor B Cell-Derived IL-10 Ameliorates Murine Graft-Versus-Host Disease

Allogeneic hematopoetic stem cell transplantation (HSCT) is the treatment of choice for a variety of hematologic malignancies. Graft-versus-Host disease (GvHD) is a key contributor to treatment related morbidity and mortality and consequently limits the efficacy of allogeneic HSCT. Interleukin 10 (IL-10) is a well-known cytokine with immunoregulatory and anti-inflammatory properties, also important in context of GvHD. B cells have been described as potent IL-10 producers in various situations. Here we show how host as well as donor derived B cells contribute to GvHD amelioration through IL-10 production.

We address the role of IL-10 in GvHD in an acute murine MHC mismatch model: Mice on a C57BL/6 background received bone marrow and CD90⁺ T cells from mice on a BALB/c background or vice versa. Transplantation experiments with IL-10 deficient donor or host cells clearly show the importance of donor derived IL-10 in general. To further dissect the cells contributing to IL-10 production in this situation we employed an IL-10 knock-in reporter mouse in which expression of eGFP is under control of the Il-10 locus. Lethal irradiation as used in the conditioning regiment before transplantation revealed B cells as major contributors of host derived IL-10. In addition, transfer of cells from reporter mice into preconditioned recipients showed also donor B cells as contributors to IL-10 production. A phenotypical characterization of the eGFP⁺ B cells exhibited a CD1d⁺TIM-1⁺CD5^int phenotype, in line with immunoregulatory B cells. To finally confirm the relevance of B cells derived IL-10 in GvHD, we employed B6.B-IL-10^-/- mice that have a B cell specific IL-10 knock-out as donors or recipients. Here we found a reduced survival associated with the incapability of the B cells to produce IL-10 in both cases.

Taken together, our results provide new insights in the mechanisms and the variety of cells contributing to the course of GvHD. An improved understanding of these aspects might help to pave the way for new treatment options to overcome current limitations of allogenic HSCT.