Discovery of Microchimerism
The Epilogue of Dr. Starzl’s autobiography, The Puzzle People, describes the beginning of his effort in 1991 to piece together the grand design by which a donor’s organ is accepted by the recipient. Now 65 years old, he had stopped performing surgery and had time to focus on the question. The new effort was grounded on Starzl’s 35 years of observations in his animal experiments and in his thousands of human kidney, liver, and other kinds of organ recipients. The initiative could be divided into four phases: (1) the discovery of microchimerism in organ transplant recipients, (2) development from the findings of a unified paradigm of transplantation immunology, (3) the extension of his concepts beyond transplantation, and (4) and his proposal of treatment regimens for organ transplantation that reduced the need for toxic immunosuppression.
In preparation for the first step, Starzl spend the better part of a year evaluating the vast, but for the most part incomprehensible, literature on the subject of alloengraftment. The possibility that organ recipients possessed donor leukocyte chimerism had not been suggested a single time in the preceding third of a century. However, there had been clues of its presence in the early Colorado kidney and liver recipients, and in current studies in rodents by Dr. Starzl’s colleague, Dr. Noriko Murase (Figure 1). After compiling the tantalizing bits of information, Starzl’s conclusion was that donor leukocytes must be present in long-surviving organ recipients. This was confirmed in April and May 1992 by the discovery with sensitive immunocytochemical and molecular (DNA) techniques of small numbers of multilineage donor leukocytes (microchimerism) in tissues and blood samples of 30 of 30 long-surviving liver (Figure 2) or kidney recipients [ref 1, 2]. Supportive evidence was systematically obtained from animal studies. [ref 3, 4]
The microchimerism discoveries had seismic implications in transplantation immunology as well as in all other branches of immunology. Before 1992, the immunity of organ transplantation had been viewed as a single host versus graft (HVG) response (Figure 3, Panel A). This explained organ rejection but not organ engraftment. After the microchimerism discoveries of 1992, organ alloengraftment could be defined by interactions of donor and recipient immune cells (Panel C, central portion of field). At about the same time, the relation of bone marrow transplantation and organ transplantation was clarified with the discovery in Seattle that bone marrow recipients who previously had been thought to have complete replacement of their immune cells (Panel B) actually had a small residual population of their own cells (Panel D).
Recognition that bone marrow and organ recipients had mirror image chimerism unified the immunology of organ and bone marrow transplantation (Figure 4). The findings and their interpretation were initially controversial because they were incompatible with much of the historical foundation of transplantation immunology. However, no revisions of the original articles have been required in the ensuing 2 decades. By January 2012, the 1992 report in Lancet [ref 1] and its Addendum in a succeeding issue had been cited 1147 times (ISI, Philadelphia). A 1993 article in Hepatology with more complete data [ref 2] had been cited nearly 600 times. A 1993 article in Hepatology with more complete data [ref 2] had been cited nearly 600 times. This is graphically illustrated in Figure 5 and the citation frequencies of all of Starzl's papers fitting into this catgory are summarized in Figure 6. Figure 7 shows a heat map analyzing each of these publications in terms of annual citation frequency.
- Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M: Cell migration, chimerism, and graft acceptance. Lancet 339:1579-1582, 1992.
- Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, Ramos H, Todo S, Tzakis A, Fung JJ, Nalesnik M, Zeevi A, Rudert WA, Kocova M: Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology 17:1127-1152, 1993.
- Murase N, Starzl TE, Tanabe M, Fujisaki S, Miyazawa H, YE q, Delaney CP, Fung JJ, Demetris AJ: Variable chimerism, graft versus host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to Brown-Norway rats. Transplantation 60:158-171, 1995.
- See The Discovery of Microchimerism Appendix for complete references and rank order citations
Four of the 6 authors of the 1992 Lancet report. Left to right: A.J. Demetris, N. Murase, T.E. Starzl, and M. Trucco. Not shown: Camillo Ricordi and Suzanne Ildstad.
The view of transplantation immunology before the microchimerism discoveries (upper panels) and afterwards (lower panels)
Overall annual citation frequency for the group of publications within the Discovery of Microchimerism Theme