Browsing by Author "Knechtle, Stuart"

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Open Access
Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients.
(American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2020-10) Dangi, Anil; Yu, Shuangjin; Lee, Frances T; Burnette, Melanie; Knechtle, Stuart; Kwun, Jean; Luo, Xunrong
Allosensitization constitutes a major barrier in transplantation. Preexisting donor-reactive memory T and B cells and preformed donor-specific antibodies (DSAs) have all been implicated in accelerated allograft rejection in sensitized recipients. Here, we employ a sensitized murine model of islet transplantation to test strategies that promote long-term immunosuppression-free allograft survival. We demonstrate that donor-specific memory T and B cells can be effectively inhibited by peritransplant infusions of donor apoptotic cells in combination with anti-CD40L and rapamycin, and this treatment leads to significant prolongation of islet allograft survival in allosensitized recipients. We further demonstrate that late graft rejection in recipients treated with this regimen is associated with a breakthrough of B cells and their aggressive graft infiltration. Consequently, additional posttransplant B cell depletion effectively prevents late rejection and promotes permanent acceptance of islet allografts. In contrast, persistent low levels of DSAs do not seem to impair graft outcome in these recipients. We propose that B cells contribute to late rejection as antigen-presenting cells for intragraft memory T cell expansion but not to alloantibody production and that a therapeutic strategy combining donor apoptotic cells, anti-CD40L, and rapamycin effectively inhibits proinflammatory B cells and promotes long-term islet allograft survival in such recipients.
Open Access
Single-Center Long-Term Analysis of Combined Liver-Lung Transplant Outcomes.
(Transplantation direct, 2018-05) Freischlag, Kyle William; Messina, Julia; Ezekian, Brian; Mulvihill, Michael S; Barbas, Andrew; Berg, Carl; Sudan, Debra; Reynolds, John; Hartwig, Matthew; Knechtle, Stuart
Background:Combined lung-liver transplantation (LLT) applies 2 technically challenging transplants in 1 patient with severe 2-organ failure. Methods:Institutional medical records and United Network for Organ Sharing database were queried for patients at our institution that underwent LLT from 2000 to 2016. Results:Twelve LLTs were performed from 2000 to 2016 including 9 male and 3 female recipients with a median age of 28.36 years. Indications for lung transplantation were cystic fibrosis (8), idiopathic pulmonary fibrosis (3), and pulmonary fibrosis secondary to hepatopulmonary syndrome (1). Indications for liver transplantation were cystic fibrosis (8), alcoholic cirrhosis (1), idiopathic cirrhosis (2), and alpha-1 antitrypsin deficiency (1). Median forced expiratory volume in 1 second at transplant was 27.8% (±20.38%), and mean Model for End-Stage Liver Disease was 10.5 (±4.68). Median hospital stay was 44.5 days. Seventy-five percent of recipients had 1+ new infection during their transplant hospitalization. Patients experienced 0.68 incidences of acute rejection per year with a 41.7% (95% confidence interval, 21.3%-81.4%) probability of freedom from rejection in the first-year. Patient survival was 100% at 30 days, 91.6% at 1 year, and 71.3% at 3 years. At the time of analysis, 7 of 12 patients were alive, of whom 3 survived over 8 years post-LLT. Causes of death were primary liver graft failure (1), bronchiolitis obliterans syndrome (2), and solid tumor malignancies (2). Conclusions:Our results indicate that LLT is associated with comparable survival to other LLT series and provides a granular assessment of infectious and rejection rates in this rare population.