Abstract
Donor-specific blood transfusion (DST) can lead to significant prolongation of allograft survival in experimental animal models and sometimes human recipients of solid organs. The mechanisms responsible for the beneficial effect on graft survival have been a topic of research and debate for decades and are not yet fully elucidated. Once we discover how the details of the mechanisms involved are linked, we could be within reach of a procedure making it possible to establish donor-specific tolerance with minimal or no immunosuppressive medication. Today, it is well established that CD4+Foxp3+ regulatory T cells (Tregs) are indispensable for maintaining immunological self-tolerance. A large number of animal studies have also shown that Tregs are essential for establishing and maintaining transplantation tolerance. In this paper, we present a hypothesis of one H2-haplotype-matched DST-induced transplantation tolerance (in mice). The formulated hypothesis is based on a re-interpretation of data from an immunogenetic experiment published by Niimi and colleagues in 2000. It is of importance that the naïve recipient mice in this study were never immunosuppressed and were therefore fully immune competent during the course of tolerance induction. Based on the immunological status of the recipients, we suggest that one H2-haplotype-matched self-specific Tregs derived from the transfusion blood can be activated and multiply in the host by binding to antigen-presenting cells presenting allopeptides in their major histocompatibility complex (MHC) class II (MHC-II). We also suggest that the endothelial and epithelial cells within the solid organ allograft upregulate the expression of MHC-II and attract the expanded Treg population to suppress inflammation within the graft. We further suggest that this biological process, here termed MHC-II recruitment, is a vital survival mechanism for organs (or the organism in general) when attacked by an immune system.
Highlights
Today, transplantation tolerance in humans who receive an organ from a genetically disparate donor can very rarely be achieved without life-long administration of immunosuppressive therapy
We have introduced a novel hypothesis on DSTinduced transplantation tolerance based on a re-interpretation of a 17-year-old immunogenetic study by Niimi et al. [13]
We hereby confirm that all the authors’ contribution to this manuscript meets with the criteria of authorship demanded by Frontiers
Summary
Transplantation tolerance in humans who receive an organ from a genetically disparate donor can very rarely be achieved without life-long administration of immunosuppressive therapy. The many successful approaches in experimental animal models have failed when attempted in humans [4, 5], there are cases of drug-free humans carrying well-tolerated organs, such as kidneys and livers, from genetically disparate donors [6, 7]. These rare cases of spontaneous tolerance ( termed operational tolerance) to a foreign organ provide hope that transplantation tolerance with no or minimal immune-suppressive medication can be achieved in humans. We re-interpret an immunogenetic experiment conducted 17 years ago by Niimi et al, and we present a hypothesis that suggests that actively involved donor blood-derived Tregs and the donor organ itself are crucial for the prolongation of the allograft survival achieved in their study
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