Therapies for Chronic Allograft Rejection

Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused by de novo donor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.

M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection

Allograft functional failure due to acute or chronic rejection has long been a major concern in the area of solid organ transplantation for decades. As critical component of innate immune system, the macrophages are unlikely to be exclusive for driving acute or chronic sterile inflammation against allografts. Traditionally, macrophages are classified into two types, M1 and M2 like macrophages, based on their functions. M1 macrophages are involved in acute rejection for triggering sterile inflammation thus lead to tissue damage and poor allograft survival, while M2 macrophages represent contradictory features, playing pivotal roles in both anti-inflammation and development of graft fibrosis and resulting in chronic rejection. Macrophages also contribute to allograft vasculopathy, but the phenotypes remain to be identified. Moreover, increasing evidences are challenging traditional identification and classification of macrophage in various diseases. Better understanding the role of macrophage in chronic rejection is fundamental to developing innovative strategies for preventing late graft loss. In this review, we will update the recent progress in our understanding of diversity of macrophage-dominated innate immune response, and reveal the roles of M2 macrophages in chronic allograft rejection as well.

Abstract 12932: The ABO Blood Group of Donor Hearts Determine the Impact of Cold Preservation Duration on Heart Transplant Outcomes

Background: Tolerance of donor hearts of different ABO blood types to allograft ischemic time has not been previously examined. Objectives: We determined the impact of allograft ischemic time on heart transplant outcomes with differing ABO donor organ types. Methods: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous variables were analyzed with t-test and categorical variables were compared with Chi-squared test. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables. Results: Comparing allograft ischemic times <4 hours (hr, n=6579) versus ≥4hr (n=25,875), the odds ratio (OR) for death at 15 years following prolonged allograft ischemic time (≥4hrs) for blood type O, A, B, and AB were 1.106 (P<0.001), 1.062 (P<0.001), 1.059 (P=0.062), 1.114 (P=0.221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for allograft ischemic times ≥4 hours (OR=1.164, P<0.001). Following propensity matching, O donor hearts continued to have worse survival if preserved for ≥4hrs (OR=1.137, P=0.008), but not if allograft ischemic time was <4hrs (OR=1.042, P=0.113). In a matched group with ≥4hrs of allograft ischemic time, patients receiving O donor organs were more likely to experience death from primary allograft dysfunction (2.5% vs 1.7%, P=0.052) and chronic allograft rejection (1.9% versus 1.1%, P=0.021). No difference in death from primary allograft graft dysfunction or chronic allograft rejection was seen with <4hr of allograft ischemic time (P>0.150). Conclusions: Compared with non-O hearts, transplantation with O donor hearts stored for ≥4hrs leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when extended cold preservation times are anticipated.

Mesenchymal Stem Cells Derived From Adipose Tissue Ameliorate Chronic Allograft Rejection In The Long Term In A Rat Experimental Model Of Kidney Transplantation

Chronic allograft nephropathy remains the leading cause of late allograft failure after renal transplantation. Current immunosuppressive regimens significantly reduce the incidence of acute rejection but do not influence long-term graft survival