Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection.

BACKGROUNDRejection is the primary barrier to broader implementation of vascularized composite allografts (VCAs), including face and limb transplants. The immunologic pathways activated in face transplant rejection have not been fully characterized.METHODSUsing skin biopsies prospectively collected over 9 years from 7 face transplant patients, we studied rejection by gene expression profiling, histology, immunostaining, and T cell receptor sequencing.RESULTSGrade 1 rejection did not differ significantly from nonrejection, suggesting that it does not represent a pathologic state. In grade 2, there was a balanced upregulation of both proinflammatory T cell activation pathways and antiinflammatory checkpoint and immunomodulatory pathways, with a net result of no tissue injury. In grade 3, IFN-γ-driven inflammation, antigen-presenting cell activation, and infiltration of the skin by proliferative T cells bearing markers of antigen-specific activation and cytotoxicity tipped the balance toward tissue injury. Rejection of VCAs and solid organ transplants had both distinct and common features. VCA rejection was uniquely associated with upregulation of immunoregulatory genes, including SOCS1; induction of lipid antigen-presenting CD1 proteins; and infiltration by T cells predicted to recognize CD1b and CD1c.CONCLUSIONOur findings suggest that the distinct features of VCA rejection reflect the unique immunobiology of skin and that enhancing cutaneous immunoregulatory networks may be a useful strategy in combatting rejection.Trial registrationClinicalTrials.gov NCT01281267.FUNDINGAssistant Secretary of Defense and Health Affairs, through Reconstructive Transplant Research (W81XWH-17-1-0278, W81XWH-16-1-0647, W81XWH-16-1-0689, W81XWH-18-1-0784, W81XWH-1-810798); American Society of Transplantation's Transplantation and Immunology Research Network Fellowship Research Grant; Plastic Surgery Foundation Fellowship from the American Society of Plastic Surgeons; Novo Nordisk Foundation (NNF15OC0014092); Lundbeck Foundation; Aage Bangs Foundation; A.P. Moller Foundation for the Advancement of Medical Science; NIH UL1 RR025758.

Kidney Dysfunction After Vascularized Composite Allotransplantation.

BACKGROUND: Kidney dysfunction is a major complication after nonrenal solid organ transplants. Transplantation of vascularized composite allografts (VCA) has yielded successful midterm outcomes despite high rates of acute rejection and greater requirements of immunosuppression. Whether this translates in higher risks of kidney complications is unknown. METHODS: Ninety-nine recipients of facial or extremity transplants from the Brigham and Women's Hospital (BWH) and the International Registry on Hand and Composite Tissue Transplantation (IR) were reviewed. We assessed immunosuppression, markers of renal function over time, as well as pretransplant and posttransplant renal risk factors. RESULTS: Data were obtained from 10 patients from BWH (age at transplant, 42.5 ± 13.8 years) and 89 patients (37.8 ± 11.5 years) from IR. A significant rise in creatinine levels (BWH, P = 0.0195; IR, P < 0.0001) and drop in estimated glomerular filtration rate (GFR) within the first year posttransplant was observed. The BWH and IR patients lost a mean of 22 mL/min GFR and 60 mL/min estimated GFR in the first year, respectively. This decrease occurred mostly in the first 6 months posttransplant (BWH). Pretransplant creatinine levels were not restored in either cohort. A mixed linear model identified multiple variables correlating with renal dysfunction, particularly tacrolimus trough levels. CONCLUSIONS: Kidney dysfunction represents a major complication posttransplantation in VCA recipients early on. Strategies to mitigate this complication, such as reducing calcineurin inhibitor trough levels or using alternative immunosuppressive agents, may improve long-term patient outcomes. Standardizing laboratory and data collection of kidney parameters and risk factors in VCA patients will be critical for better understanding of this complication.

Tissue conservation for transplantation.

Pathophysiological changes that occur during ischemia and subsequent reperfusion cause damage to tissues procured for transplantation and also affect long-term allograft function and survival. The proper preservation of organs before transplantation is a must to limit these injuries as much as possible. For decades, static cold storage has been the gold standard for organ preservation, with mechanical perfusion developing as a promising alternative only recently. The current literature points to the need of developing dedicated preservation protocols for every organ, which in combination with other interventions such as ischemic preconditioning and therapeutic additives offer the possibility of improving organ preservation and extending it to multiple times its current duration. This review strives to present an overview of the current body of knowledge with regard to the preservation of organs and tissues destined for transplantation.