Targeting Siglecs on Recipient Antigenpresenting Cells With Sialic Acid-Modified Alloantigen to Promote Transplantation Tolerance

Chronic transplant rejection remains a persistent barrier to transplant survival. One approach to tackle this is to target the indirect pathway of allorecognition, the major contributor to chronic mediated rejection. Modifying the recipient’s antigen- presenting cells which have a major role of presenting graft-derived donor alloantigens to recipient T cells, which proliferate and differentiate into effector cells thereby leading to an immune attack against the transplanted organ, has been undertaken. Previous studies found that targeting alloantigens derived from BALB/c MHC Class I H-2Kᵈ via specific cell surface receptors to immature dendritic cells (DCs), impaired indirect allorecognition leading to murine skin grafts survival. Siglec receptors have previously been targeted on murine DCs to induce tolerance in an autoimmune mouse model. These receptors specifically bind to sialylated ligands and have a role in downregulating immune responses due to their immunoreceptor tyrosine-based inhibitory motif. To date, it has not been established whether targeting these receptors can induce transplantation tolerance; therefore our aim was to target Siglecs on a heterogeneous population of recipient DCs with sialylated H-2Kᵈ alloantigen to modify the indirect pathway of allorecognition and to promote organ transplant survival.
In this study it was established Siglecs were expressed on DCs, B cells and macrophages. Targeting sialylated alloantigen to DCs impaired indirect alloreactive CD4⁺ T cell proliferation and cytokine production; and were able to induce/expand CD4⁺ Foxp3⁺ Tregs in vitro following targeting.
Additionally, we have demonstrated in vivo that sialylated alloantigen treatment prior to MHC-mismatch donor skin transplantation to wild-type B6 recipient mice resulted in graft prolongation and also a significant increase of CD4⁺ CD62L⁺ Foxp3⁺ Tregs in recipient blood, a possible contributor to the observed graft survival. In addition, there was a marked decrease of alloantibodies, signifying that alloreactive B cells activated via indirect pathway of allorecognition are being inhibited. This was attributed to Siglec expression on DCs requiring Batf3 transcription factor for their development (CD103⁺ and CD8α⁺ DCs). It was also observed that mice treated with sialylated alloantigen deleted indirect CD4⁺ T cells in vivo, suggesting that this could be one of the mechanisms contributing to allograft survival.
In conclusion, targeting recipient DCs with sialylated alloantigen may represent a novel mechanism to regulate allorecognition and prolong allograft survival.