A History of Organ Transplantation: Ancient Legends to Modern Practice

6 The “Lost Era” of Transplantation Immunology

105 6 The “Lost Era” of Transplantation Immunology A wareness of the phenomenon later called “immunity” existed in ancient times.¹ After epidemics, those who recovered from the disaster seemed naturally protected from future outbreaks of the illness. Possibly in India or China, early peoples learned to induce a state of immunity to smallpox by inoculation—placing a small amount of material from mildly affected patients onto scratches in the skin of others at risk, who later usually did not experience the full effects of the disease. The strategy was observed in use in Turkey in the early 1700s and was brought back to Europe and used with success. To add to this method, Edward Jenner later became aware of the protective effect of cowpox against smallpox. In the effort to explain immunity, the first contributions from the laboratories were unhelpful. Louis Pasteur believed that the difficulty in growing microorganisms outside the body for any length of time meant that these bacteria required “growth factors,” which, when exhausted, meant that the organisms failed to thrive. This theory he applied to the intact mammalian body, arguing that organisms invading the body ran out of an essential nutrient and died, rather than succumbing due to a defensive response of the body. The Humoral School This “exhaustion” or “athrepsia” theory of immunity was put aside after Emil von Behring and Shibasaburo Kitasato’s crucial demonstration in 1890 of the appearance of protective circulating antitoxins in cases of diphtheria and tetanus. It was accordingly proposed that, in general, microorganisms assaulted the body via a toxin (antigen), and the body defended itself by an antitoxin (antibody), that is, a chemical, “humoral” mechanism. On a second exposure to the toxin, production of the anti- 106 The “Lost Era” of Transplantation Immunology body was found to be faster and greater. This “secondary response” and the “memory” involved were taken as the hallmarks of an immunological reaction.² Paul Ehrlich (1854–1915) usefully broadened the role of the antibody, suggesting that it could appear as a response to many invaders, indeed any protein, not just the familiar pathogenic microorganisms that dominated clinical work at the time.³ Cellular Immunology This “humoral” school was not unopposed. An alternative view emerged to suggest that cellular mechanisms—phagocytes and other scavenging cells of the newly identified reticuloendothelial system—were involved in the defense of the host, and Elie Metchnikoff (1845–1916) and his followers vigorously advocated this proposal. The debate over the roles played by these defense mechanisms proceeded in Europe in a partisan and chauvinistic way, lining up French scientists (cellular supporters) against Germans (humoral mechanism advocates). The view that Metchnikoff’s cellular system was the primary and only defense mechanism lost ground steadily, and, as a compromise, Metchnikoff’s phagocytic system was later accommodated into a dual partnership, one part (humoral) with speci- ficity and memory and the other (cellular) without those attributes. This harmony was blessed with the joint award of the Nobel Prize in 1910 to Ehrlich and Metchnikoff. Immunology and Transplantation We can admire these contributions of Ehrlich to basic immunology, but when he changed direction to study reactions to tissue transplantation, his contribution was initially less than helpful. In 1903, Ehrlich plunged into a study of the behavior of tissue transplants, using the newly described transplantable mouse tumors. This leap overlooked a crucial first step, one that later became obvious: thoroughly studying the immunology of normal mouse tissue acceptance or loss. The existence of these animal tumors had been known for some time, but their study was to cause decades of difficulty in understanding immunological responses to normal tissue grafts. In 1806, the Medical Committee of the Society for Investigating the Nature and Cure of Cancer, based in London, defined the aims of its proposed research.⁴ The committee reported that “it is not at present known whether brute creatures are subject to cancer, though some of their distresses have a very suspicious appearance. When this question is decided, we may inquire what class of animals is chiefly subject to cancer. . . . As establishments are now formed for the reception of several kinds of animals, and as the treatment The “Lost Era” of Transplantation Immunology 107 of their diseases has at length fallen under the care of scientific men, it is hoped that the information here required may be readily obtained .”⁵ The first comprehensive study of animal tumors...