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B lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and Ab production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to downregulate unwanted immune responses, such as transplant rejection. In this study, we found that PMA- and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through TLR4/TLR9 receptors (Bregs-TLR). Bregs-TLR efficiently inhibited T cell proliferation in vitro and prevented allograft rejection. Unlike most reported Breg activities, the inhibition of alloimmune responses by Bregs-TLR relied on the expression of TGF-β and not IL-10. In vivo, Bregs-TLR interrupted donor-specific T cell expansion and induced Tregs in a TGF-β–dependent manner. RNA-Seq analyses corroborated the involvement of TGF-β pathways in Breg-TLR function, identified potential gene pathways implicated in preventing graft rejection, and suggested targets to foster Breg regulation.

Although efforts have been made by transplant centers to increase the pool of available livers by extending the criteria of liver acceptance, this practice creates risks for recipients that include primary non-function of the graft, early allograft dysfunction and post-operative complications. Donor liver machine perfusion (MP) is a promising novel strategy that not only decreases cold ischemia time, but also serves as a method of assessing the viability of the graft. In this review, we summarize the data from liver machine perfusion clinical trials and discuss the various techniques available to date as well as future applications of machine perfusion. A variety of approaches have been reported including hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP); the advantages and disadvantages of each are just now beginning to be resolved. Important in this effort is developing markers of viability with lactate being the most predictive of graft functionality. The advent of machine perfusion has also permitted completely ischemia free transplantation by utilization of in situ NMP showed promising results. Animal studies that focus on defatting steatotic livers via NMP as well as groups that work on regenerating liver tissue ex vivo via MP. The broad incorporation of machine perfusion into routine clinical practice seems incredible.