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Background: It is estimated that 25%-35% of heart transplant recipients develop de novo donor-specific antibodies (dnDSA). One factor that appears to play a role in clinical outcomes is DSA persistence. The objective of this study was to determine the incidence of transient and persistent dnDSA in a Canadian heart transplant population and to evaluate their impact on coronary allograft vasculopathy (CAV), graft function, and mortality., Methods: A retrospective study of consecutive adult and transitioned pediatric heart transplant recipients (2008-2015) in Toronto was performed. Clinical demographics were collected prospectively. HLA antibody testing was performed using Luminex single antigen assays. In statistical analysis, dnDSA was modeled as a time dependent covariate., Results: During a median follow-up of 4.1 years, dnDSA were detected in 42 (23%) with a median time to detection of 329 days (156-740); 27 (64%) developed persistent dnDSA. Persistent dnDSA conferred an increased risk of death with a HR 4.0 (95%CI 1.4-12.1) when adjusted recipient age, CAV, and cytomegalovirus status., Conclusions: Transient dnDSA were not associated with adverse outcomes after heart transplantation. This suggests that transient dnDSA may not require enhanced immunosuppression, increased HLA antibody monitoring, or additional physiological assessment. By knowing the transient dnDSA status, clinicians may minimize both recipient morbidity and cost without increasing harm., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The objective of this study was to evaluate systemic immunosuppression regimens used for patients undergoing ocular surface stem cell transplantation, including their benefits and adverse effects in the adjunctive management of limbal stem cell deficiency (LSCD). A systematic literature review was conducted using the MEDLINE and EMBASE databases (1980-2015). Data were collected on surgical intervention(s), type of immunosuppressive agent(s), duration of immunosuppression, percentage with stable ocular surface at last follow-up, mean follow-up time, and demographics. Data were also collected on adverse ocular and systemic outcomes. Sixteen reports met the inclusion criteria. There were no randomized controlled studies. Three studies were noncomparative prospective case series, whereas the majority were retrospective case series. Bilateral severe LSCD was the most common disease (50%), and keratolimbal allograft was the most common intervention (80%). Immunosuppressive regimens showed a progression from early studies using oral cyclosporine to later studies using combinations of mycophenolate mofetil and tacrolimus. Most studies included a course of high-dose systemic corticosteroids. For patients adherent to long-term systemic immunosuppression, stable ocular surface rates of 70%-80% at last follow-up were reported. Adverse effects included hypertension, diabetes mellitus, and biochemical abnormalities managed with pharmacotherapy or discontinuation of offending agents. There were no cases of mortality related to immunosuppression. However, the current literature does not elucidate which immunosuppressive regimen is most efficacious for different categories of LSCD or graft types. Evidence-based guidelines for systemic immunosuppression in limbal allograft therapy would benefit from randomized controlled and/or additional prospective studies. Long-term immunosuppression would benefit from close collaboration between ophthalmologists and transplant specialists to individualize treatments., (Copyright © 2018. Published by Elsevier Inc.)

Kidney retransplantation is a risk factor for decreased allograft survival. Repeated mismatched HLA antigens between first and second transplant may be a stimulus for immune memory responses and increased risk of alloimmune damage to the second allograft. Historical data identified a role of repeated HLA mismatches in allograft loss. However, evolution of HLA testing methods and a modern transplant era necessitate re-examination of this role to more accurately risk-stratify recipients. We conducted a contemporary registry analysis of data from 13,789 patients who received a second kidney transplant from 1995 to 2011, of which 3868 had one or more repeated mismatches. Multivariable Cox proportional hazards modeling revealed no effect of repeated mismatches on all-cause or death-censored graft loss. Analysis of predefined subgroups, however, showed that any class 2 repeated mismatch increased the hazard of death-censored graft loss, particularly in patients with detectable panel-reactive antibody before second transplant (hazard ratio [HR], 1.15; 95% confidence interval [95% CI], 1.02 to 1.29). Furthermore, in those who had nephrectomy of the first allograft, class 2 repeated mismatches specifically associated with all-cause (HR, 1.30; 95% CI, 1.07 to 1.58) and death-censored graft loss (HR, 1.41; 95% CI, 1.12 to 1.78). These updated data redefine the effect of repeated mismatches in retransplantation and challenge the paradigm that repeated mismatches in isolation confer increased immunologic risk. We also defined clear recipient categories for which repeated mismatches may be of greater concern in a contemporary cohort. Additional studies are needed to determine appropriate interventions for these recipients., (Copyright © 2016 by the American Society of Nephrology.)

The role of alloantibodies against HLA and non-HLA targets is becoming increasingly recognized as critical in the pathogenesis of acute and chronic renal allograft outcomes. This review discusses the antigenic targets, the mechanisms of T and B cell activation that result in the production of antibody, the complement cascade, methods of antibody detection, and the evidence that alloantibody-mediated mechanisms are active in acute and chronic rejection.

Background: Diffuse peritubular capillary (PTC) C4d deposition has been shown to be associated with relatively poor graft outcome. The significance of focal PTC C4d staining in the early post-transplant period is uncertain., Methods: Sixty-five biopsies from 53 patients with acute rejection were graded (Banff '97 criteria), stained for C4d, monocytes and T cells, and divided into three groups according to PTC C4d: (i) focal C4d (F) (14 biopsies, 14 patients), (ii) diffuse C4d (D) (23 biopsies, 15 patients) and (iii) no C4d (N) (28 biopsies, 24 patients). The three groups were compared with respect to a variety of biopsy and clinical parameters including outcome., Results: The incidence of transplant glomerulitis and glomerular monocyte infiltration were significantly greater in F (64% and 2.0+/-2.0) and D (57% and 3.4+/-2.0) than in N (11% and 0.2+/-0.2). A significantly higher proportion of F (93%) demonstrated acute cellular rejection (Banff '97 grade > or = 1A) than did D (35%). The F and D groups included significantly more females (50 and 67%, respectively) than did N (21%). The percentage of patients with a second or third transplant was higher in F (29%) and D (40%) than in N (8%) (P = 0.0589). The proportion of patients with glomerular filtration rate < 30 ml/min at 12, 24 and 48 months was higher in the D and F groups than in the N, and there was a statistically significant increasing trend in odds of this outcome occurring at 48 months across the three groups (D > F > N group) (P = 0.0416)., Conclusion: The results suggest that the biopsy findings and clinical course in patients with focal PTC C4d staining are similar to those associated with diffuse C4d.

Background: Both peritubular capillary (PTC) C4d deposition and macrophage/monocyte (MO) infiltration in acute rejection (AR) have separately been shown to be associated with reduced graft survival and recently were demonstrated to be closely correlated in AR. Whether MO infiltration is an independent predictor of graft outcome is uncertain., Methods: All patients with biopsy-proven AR (over a 3-year period) were included (N= 96). All biopsies (N= 121) were graded according to the Banff 97 criteria and immunohistochemically stained for C4d and MO (CD68). The primary outcome was glomerular filtration rate (GFR) <30 mL/min 1-year posttransplant as estimated by the Modified Diet in Renal Disease (MDRD) Formula. Secondary outcomes at 2 and 4 years' posttransplant were also explored. A variety of clinical and biopsy variables were statistically analyzed to establish univariate predictors of graft outcome. Stepwise multivariate logistic regression modeling was applied to determine independent predictors of outcomes., Results: There was a close correlation between PTC C4d and glomerular MO infiltration (P < 0.001). Univariate predictors of primary outcome (GFR <30 mL/min 1-year posttransplant) included mean glomerular MO count > or =1.0 MO/glomerulus (P= 0.014), female sex (P= 0.02), higher peak (P= 0.005), and pretransplant (P= 0.003) panel-reactive antibody levels, cadaveric donor (P= 0.006), transplant glomerulitis (P= 0.004), and longer cold ischemic time (CIT) (P= 0.002). Mean MO/glomerulus > or =1.0 [OR 10.3 (1.23, 87.1)], female sex [OR 5.27(1.31, 21.1)], and CIT [OR 1.14 (1.06, 1.25)] were identified as independent predictors of adverse graft outcome. Furthermore, mean MO/glomerulus > or =1.0 independently predicted poor renal function at 2 years [OR 3.89 (1.19, 12.70)] and 4 years [OR 4.03 (1.22, 13.28)] posttransplant., Conclusion: The results demonstrate that glomerular MO infiltration is an independent predictor of worse outcomes posttransplant following acute renal allograft rejection.

Clinical transplantation tolerance has remained an elusive goal in the 50 yr since it was first described in experimental animals. Greater understanding of the molecular mechanisms responsible for allorecognition have allowed for the development of promising immunosuppressive strategies that may bring us closer to reproducible induction of tolerance; consideration of past successes and failures from both clinical and basic science is required to define future challenges facing this field. This article reviews mechanisms of self and transplantation tolerance, translation of basic science research to clinical protocols in animals and human beings, the changing role of immunosuppression, complications following tolerance induction and controversies surrounding the choice of patients for tolerance trials with a focus on issues relevant to pediatric patients. The role of the Immune Tolerance Network is discussed along with realistic goals for tolerance induction in human beings over the next decade.

Summary: The impact of donor specific HLA antibodies (DSA) on solid organ transplant outcomes has been recognised for over half a century. This article reviews the mechanisms of DSA formation, details the laboratory methods for detecting DSA, discusses the clinical and histological manifestations of DSA in the allograft and explores the options for management of DSA. The challenges posed by pre‐existing and de novo DSA are explored with current therapeutic strategies described. A method for stratifying the risk associated with pre‐existing DSA is explained and the importance of understanding immunological risk associated with transplantation to facilitate optimal personalised decision making for transplant recipients is highlighted. Future directions for further managing the risk associated with DSA are proposed. [ABSTRACT FROM AUTHOR]