"Humoral theory of transplantation and Dr. Paul Terasaki: a personal view"
Adriana Zeevi, Ph.D.

Dr. Terasaki has been and continues to be a great inspiration for many generations of histocompatibility and transplant immunologists. I had the honor of meeting Dr. Terasaki during the 1980 International Histocompatibility Workshop in Los Angeles. I was a newcomer, having arrived in this country just 6 months earlier, new to the world of HLA, and I was hooked. For the next 20 years I dedicated my research efforts to monitoring of thoracic solid organ transplants from the cellular prospective and learning about the effects of various immunosuppressive drugs, but I continued to follow closely the tremendous advances, particularly in renal transplantation, of the role of HLA antibody on allograft outcome. The seminal publication from Dr. Terasaki, “Humoral Theory of Transplantation”, published in American Journal of Transplantation (2003), opened the door to investigate the role of HLA antibodies in all solid organ transplants. I was inspired by his determination to prove the humoral theory of transplantation and by his challenge to the rest of us, that “the purpose of a theory is to stimulate research providing its validity” (1).
Major advances in understanding the role of HLA antibodies detected pre- and post-transplant on allograft outcome came from the International Workshops organized and supported by Dr. Terasaki. Among the 45 centers that participated in the 14th IHIWS Prospective Chronic Rejection Study, (Melbourne 2005, only our center and one other reported on the frequency of HLA antibodies in lung transplantation (2). In this report, Dr. Terasaki emphasized the need to follow patients after the detection of HLA antibody, and the data from lung transplant patients confirmed the strong correlation with the presence of donor-specific HLA antibodies (DSA) in circulation prior to graft failure (2). However, because of the small number of patients and few centers that monitored lung transplant recipients, it took another decade to reach consensus in the field and change the headline from “Antibody rejection in lung transplantation: Myth or Reality” (3) to “Consensus report on diagnostic criteria for lung antibody mediated rejection” (4). I always appreciated Dr. Terasaki’s encouragement to compile evidence that DSA may precede the development of chronic rejection as manifested in lung allografts by the development of bronchiolitis obliterans (5).
With increased sensitivity and specificity of DSA detection using Luminex single antigen bead testing, HLA antibodies have been shown to be predictive of subsequent graft failure in kidney, heart, lung, liver, small bowel, and islet transplants (6). A decade after this first publication, Dr. Terasaki outlined in his personal perspective of humoral theory the next challenge: “It now remains for the clinicians to use this new tool to monitor patients after transplantation, and to remove the antibodies, if found. This should lead to the day when some changes in long-term graft survival of organs will finally be achieved” (6).
With this directive, Dr. Terasaki once again paved the way for transplant professionals to focus on antibody removal therapies as the next significant development for improving long term allograft outcome.

1. Paul I Terasaki: Humoral Theory of Transplantation. American Journal of Transplantation 2003; 3:665-673
2. Ozawa M, Terasaki PI, Lee JH et al: 14th International HLA Immunogenetics Workshop: Report on the Prospective Chronic rejection Project Tissue Antigens 2007; 1: 174-179
3. Allan Glanville: Antibody rejection in lung transplantation: Myth or reality. Journal of Heart and Lung Transplantation 2010.; 29: 395-400
4. Levine DJ, Glanville AR, Aboyoun C et al: Antibody-Mediated rejection of the lung: A Consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant, 2016; 35: 397-406
5. Morrell M, Pilewski MJ, Gries JC, et al :De novo donor-specific HLA antibodies are associated with early grade bronchiolitis obliterans syndrome and death after lung transplantation J Heart Lung Transplant 2014; 33: 1288-1294
6. Paul I Terasaki: A personal Perspective: 100 Year History of the Humoral Theory of Transplantation. Transplantation 2012; 93: 751-756

Adriana Zeevi PhD (D) ABHI
Professor of Pathology, Surgery and Immunology
Director of Tissue Typing Laboratory
University of Pittsburgh Medical Center
Room 4033, Clinical Laboratory Building
3477 Euler Way , Pittsburgh, PA 15213
Phone: 412-647-6266
Fax: 412-647-7741
Email: zeevia@upmc.edu