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Role of ß3 Integrin in Acute Renal Allograft Rejection in Humans

Arun Chandrakantan^*, David H. McDermott, Huong Thi Bich Tran, Mollie Jurewicz, Lorenzo Gallon, Robert Gaston^*, Edgar Milford, and Reza Abdi

^* Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama; Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Renal Division, Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts; and Division of Nephrology and Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Correspondence: Dr. Reza Abdi, Transplantation Research Center, Renal Division, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115. Phone: 617-732-5259; Fax: 617-732-5254; E-mail: rabdi{at}rics.bwh.harvard.edu

Background and objectives: ß3 Integrin may play a role in the process of acute rejection by increasing leukocyte adhesion to the endothelium, cytotoxic T lymphocyte activation, and platelet aggregation.

Design, setting, participants, & measurements: For investigation of the role of ß3 integrin in the pathogenesis of acute rejection, this study examined the surface expression of ß3 integrin on leukocyte subsets and analyzed a common single-nucleotide polymorphism in exon 2 of the gene encoding the ß3 subunit that generates two ß3 integrin isoforms, termed Pl^A1 and Pl^A2. Pl^A genotype was determined in blood samples from 445 renal allograft recipients at two centers. Patients were then grouped by Pl^A genotype, and clinical outcomes as recorded in a preexisting database were analyzed.

Results: Although almost all monocytes express ß3 integrin, its expression was also found on all leukocyte subsets, including T, B, and NK cells. The percentage of patients who experienced acute rejection was noted to be significantly higher in those with Pl^A1/Pl^A1 (TT) genotype versus patients with the Pl^A1/Pl^A2 or Pl^A2/Pl^A2 (CT or CC) genotypes (33% for TT versus 20% for CT or CC). In a multivariate analysis, the Pl^A1/Pl^A1 (TT) genotype remained significantly associated with acute rejection. Patients with Pl^A1/Pl^A1 (TT) genotype also exhibited a higher number of acute rejection episodes per patient.

Conclusions: The Pl^A1/Pl^A1 (TT) genotype is associated with an increased incidence of acute renal allograft rejection in humans, supporting a role for ß3 integrin in the pathophysiology of acute rejection.