Suppression of liver transplant rejection by anti-donor MHC antibodies via depletion of donor immunogenic dendritic cells

Abstract

Background We previously found two distinct passenger dendritic cell (DC) subsets in the rat liver that played a central role in the liver transplant rejection. In addition, tolerance-inducing protocol, donor-specific transfusion (DST), triggered systemic polytopical production of depleting alloantibodies to donor class I MHC antigen (DST-antibodies). Methods We examined the role of DST-antibodies in the trafficking of graft DC subsets and the alloresponses in a rat model. We also examined an anti-donor class II MHC (MHCII) antibody that recognizes donor DCs more selectively. Results Preoperative transfer of DST-antibodies and DST pretreatments eliminated all passenger leukocytes, including both DC subsets and depleted the sessile DCs in the graft to ~20% of control. The CD172a +CD11b/c + immunogenic subset was almost abolished. The intrahost direct or semi-direct allorecognition pathway was successfully blocked, leading to a significant suppression of the CD8 + T-cell response in the recipient lymphoid organs and the graft with delayed graft rejection. Anti-donor MHCII antibody had similar effects without temporary graft damage. Although DST pretreatment had a priming effect on the recipient Treg proliferative response, DST-primed sera and the anti-donor MHCII antibody did not. Conclusion DST-antibodies and anti-donor MHCII antibodies could suppress the CD8 + T-cell-mediated liver transplant rejection by depleting donor immunogenic DCs, blocking the direct or semi-direct pathway of allorecognition. Donor MHCII-specific antibodies may be applicable as a selective suppressant of anti-donor immunity for clinical liver transplantation without the cellular damage of donor MHCII – graft cells and recipient cells.

Dendritic cells in liver transplantation immune response

“…ACR is mainly a cellular immune response mediated by T cells after liver transplantation. DCs, as the most important APCs in priming T cells, they present allogeneic antigens to the cognate T-cell receptor (TCR) to activate them, thus initiating cellular immune responses (Yu et al, 2012;Ueta et al, 2021). Under homeostatic conditions, hepatic DCs exhibit an immature/anti-inflammatory phenotype, T cells are barely activated, and are less immunogenic (Bamboat et al, 2009).…”

Role of the immune system in liver transplantation and its implications for therapeutic interventions

“…MHC I has been known to promote tolerance in other organ transplantations, suggesting the potential for future gene therapy in liver transplant‐related AR 251 . Additionally, MHC antibody therapy represents a significant clinical approach for managing AR 252 . The main APCs in the liver, can capture foreign antigens and present MHC molecules through cytoplasm or exosomes to either activate or inhibit T cells 13,253–255 .…”

“… 251 Additionally, MHC antibody therapy represents a significant clinical approach for managing AR. 252 The main APCs in the liver, can capture foreign antigens and present MHC molecules through cytoplasm or exosomes to either activate or inhibit T cells. 13 , 253 , 254 , 255 Under the influence of proinflammatory factors like PRI, APCs in the donor liver upregulate their MHC expression, triggering T‐cell‐mediated immune responses.…”

Estimation of Sensitization Status in Renal Transplant Recipients by Assessing Indirect Pathway CD4+ T Cell Response to Donor Cell-pulsed Dendritic Cell

“…12,13 The mechanism of transfer of donor HLA to recipient APC, which, to date, has only been clearly demonstrated in mouse transplantation models, is still largely unknown in humans because of the difficulty of the detection system. 14 The mechanism of transfer of donor HLA to recipient APC has been proposed to be direct cell–cell contact or via exosomes released from the donor cells. 15 On the other hand, the indirect allorecognition pathway is analogous to adaptive immune responses initiated by protein Ag.…”