AbstractThe application of allogeneic stem cell transplantation (alloSCT) is limited by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic forms that likely have different requirements for initiation and pathogenesis mechanisms. In prior studies we demonstrated that residual host antigen-presenting cells (APCs) were required to initiate acute GVHD (aGVHD) mediated by CD8 T cells. In contrast, here we demonstrate that either donor or host APCs can initiate CD4-mediated GVHD in a model that has features of chronic GVHD (cGVHD). Both donor and host APCs must provide CD80/86-dependent costimulation to elicit maximal cGVHD, and there is no GVHD when both donor and host lack CD80/86. Finally, we were surprised to find that, although either donor or host APCs are sufficient to stimulate skin cGVHD, donor APCs play a dominant role in intestinal cGVHD. Both CD40 and CD80/86 are critical for donor APC function in intestinal cGVHD, but only CD80/86 is required for skin cGVHD. Thus, there are target-tissue–specific differences in APC requirements. These results identify differences in APC requirements between CD8-mediated aGVHD and CD4-mediated cGVHD. They further highlight donor APCs as additional targets for GVHD therapy.
Abstract
Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.
Abstract
The monoclonal antibody Rituximab has been successfully used to treat steroidrefractory chronic graft versus host disease (cGvH) after allogeneic stem cell transplantation (SCT). We hypothesized that Rituximab might reduce the incidence of aGvH. We found that patients conditioned with a regimen containing Rituximab experienced significantly less aGvH when compared to a regimen without Rituximab (23.1% versus 66.7%, p = 0.032). Furthermore did we find that the recovery of CD3+CD4+ lymphocytes was delayed following administration of Rituximab. As expected, patients were devoid of CD19+CD20+ B lymphocytes after administration of Rituximab; interestingly, both the recovery of CD3+CD8+ lymphocytes and CD16+CD56+ NK cells did not differ between patients receiving Rituximab and Rituximab-naíve patients. Furthermore, our data revealed a significant correlation of the transplants CD34+ HSC content with the occurrence of aGvH (p = 0.031) but only a trend towards a correlation of CD3+ cells with the occurrence of aGvH (p = 0.274). Taken together, our data establish a mechanism of how Rituximab might reduce the incidence of aGvH next to depleting host and perhaps donor antigen presenting cells. It remains to be elucidated whether this effect translates to a graft versus tumor effect and to survival as well.
Th2 Cell Therapy of Established Acute Graft-Versus-Host Disease Requires IL-4 and IL-10 and Is Abrogated by IL-2 or Host-Type Antigen-Presenting Cells