Abstract
BackgroundOff-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated.MethodsThree transplantation models were used in this study; MHC-matched, minor antigen-mismatched mouse skin or iPSC-graft transplantation, and fully allogeneic human iPSC-derived liver organoid transplantation in immune-humanized mice. The recipients were treated with triple drugs combination (TDC; tacrolimus, methylprednisolone, and mycophenolate mofetil) or co-stimulatory molecule blockade (CB) therapy with some modifications. Graft survival as well as anti-donor T and B cell responses was analyzed.ResultsIn the mouse skin transplantation model, immunological rejection caused by the minor antigen-mismatch ranged from mild to severe according to the donor-recipient combination. The TDC treatment could apparently control the mild skin graft rejection when combined with a transient T cell depletion, but unexpected anti-donor T or B cell response was observed. On the other hand, CB therapy, particularly when combined with rapamycin treatment, was capable of attenuating both mild and severe skin graft rejection and allowing them to survive long-term without any unfavorable anti-donor immune responses. The efficacy of the CB therapy was confirmed in both mouse and human iPSC-derived graft transplantation.ConclusionsThe findings suggest that the CB-based treatment seems suitable to well manage the MHC-matched allogeneic iPSC-based transplantation. The TDC-based treatment may be also used to suppress the rejection, but screening of its severity prior to the transplantation seems to be needed.
Highlights
In the field of transplantation medicine, promoting graft acceptance and prolonging graft survival are important issues because of the limited number of donors [1]
major histocompatibility complex (MHC) homo-to-hetero skin transplantation was performed using a method based on our previous report [17] where F1 (H-2b/k) mice were grafted with skin from C57BL/6 J (B6) (H-2b/b), CBA (H-2 k/k), or BALB/c (H-2d/d) mice (Fig. 1A)
Recipients were treated with a calcineurin inhibitor, inosine monophosphate dehydrogenase inhibitor, and corticosteroid, that have long been combinatory used to control on day 100 exhibited epidermal atrophy compared to autologous grafts, and hematoxylin and eosin (HE) staining analysis of paraffinembedded sections revealed skin graft hyperplasia and immune cell infiltration
Summary
In the field of transplantation medicine, promoting graft acceptance and prolonging graft survival are important issues because of the limited number of donors [1]. Major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, plays an important role in the immune response after allogeneic transplantation as they are expressed on the cell surface and undergo surveillance by recipient immune cells, especially T cells [3]. The main cause of graft loss is HLA mismatch, other antigens, such as minor antigens, can cause rejection in human [7]. Two large multicenter studies using independent registry data showed decreased long-term survival of kidney transplants performed between HLA haplotype-matched siblings, emphasizing the importance of non-HLA immunity to allogeneic grafts [8, 9]. Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have