Abstract
SummaryChronic rejection of solid organ allografts remains the major cause of transplant failure. Donor-derived tissue-resident lymphocytes are transferred to the recipient during transplantation, but their impact on alloimmunity is unknown. Using mouse cardiac transplant models, we show that graft-versus-host recognition by passenger donor CD4 T cells markedly augments recipient cellular and humoral alloimmunity, resulting in more severe allograft vasculopathy and early graft failure. This augmentation is enhanced when donors were pre-sensitized to the recipient, is dependent upon avoidance of host NK cell recognition, and is partly due to provision of cognate help for allo-specific B cells from donor CD4 T cells recognizing B cell MHC class II in a peptide-degenerate manner. Passenger donor lymphocytes may therefore influence recipient alloimmune responses and represent a therapeutic target in solid organ transplantation.
Highlights
Solid organ transplantation provides an effective therapy for patients with kidney, liver, heart, and pulmonary failure
We have shown that in a murine heart transplant model with an isolated MHC class II-mismatch [B6(C)-H2-Ab1bm12/KhEgJ to C57BL/6 (B6)], passenger bm12 CD4 T cell recognition of I-Ab MHC class II on host B cells triggers the production of antinuclear autoantibody, which causes allograft vasculopathy (Motallebzadeh et al, 2012; Win et al, 2009)
We sought to examine the impact of these passenger donor lymphocytes on recipient adaptive alloimmune responses
Summary
Solid organ transplantation provides an effective therapy for patients with kidney, liver, heart, and pulmonary failure. The precise role of NK cells in solid organ transplantation remains unclear (Gill, 2010; Hadad et al, 2014; van der Touw and Bromberg, 2010; Hidalgo et al, 2010), and early transplant studies indicate that circulating donor lymphocytes are often detectable in human transplant recipients, albeit in small numbers (Starzl et al, 1992a) Their presence may manifest as devastating, acute graft-versus-host (GVH) disease (Sharma et al, 2012), or as passenger lymphocyte syndrome, in which hemolysis is triggered by donor B cell recognition of mismatched ABO blood group antigens in the recipient (Nadarajah et al, 2013). The impact of passenger lymphocytes on the recipient immune response to the allograft has still to be clarified (Turner et al, 2014)
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