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I was recently the president of the Clinical Immunology Society. As part of my presidential address, I took out my medical school textbooks from the early 1950s. I looked over Thomas Rivers' virology textbook, the best hematology textbook, Maxwell Wintrobe, and infectious disease books. I asked, “What did we know about the immune system when these books were written?”
The T cell is the target of the AIDS virus. However, the T cell was not known in 1955; and the role of the thymus in generating small cells that are important to the immune system had not been defined at all. These small cells were virtually unmentioned other than to note that they could become a form of cancer–leukemia. Alternatively, totally aberrant statements were made in these books. It was suggested that lymphocytes might be involved in the catabolism of proteins and that they probably were not involved in carrying lipids to the liver. There was no knowledge whatsoever of their true function. I may not do total justice to people like [Dr. Merrill] Chase and others, but the general scientific community had essentially no knowledge about cellular immunity, T cells versus B cells. These concepts began to emerge in the early 1960s as individuals studying the role of the thymus–or alternatively in birds, another organ called the bursa of fabricius that is the organ for B cells that parallels the thymus in T cells–began to recognize that there are two dominant kinds of cells involved in pathways of the immune system. Incisive people like Bob [Dr. Robert] Good and [Dr.] Max Cooper began to separate the genetic human diseases along errors of the pathways of cellular interaction and cellular maturation, B-or T-cell pathways. In a very wonderful meeting in Sanibel Island, Florida, in about 1963, scientists first began to talk about these diseases in terms of the type of cell and the immune function involved.
The tests for T-cell functions emerged from various laboratories, including our own. We were the first to demonstrate suppressor T cells in human beings, and we showed that they could play a role in the immunodeficiency of patients with common variable hypogammaglobulinemia. The T-cell functions were the focus of an early phase of research. The next phase first involved the use of heteroantibodies, then of hybridoma technology and monoclonal antibodies, to define differences in the surface of T cells with different functions. CD4 and CD8 antibodies were defined. CD4, the entry site for HIV, was not known until the late 1970s when Dr. [Pat] Kung of Ortho Scientific, in conjunction with Drs. [Ellis] Reinherz and [Stewart] Schlossman of Harvard and many others, contributed by making monoclonal antibodies to this protein. We used similar monoclonal antibody approaches to define the structure of the IL-2 receptor.
By this time, one could grow B lymphocytes using the Epstein-Barr virus. But there was no way of growing T cells. Drs. [A. Charles] Morgan, [Dr. Francis] Rucetti, and Gallo tried to grow granulocytes, but with a serendipitous observation presented to their open minds, were able to define T-cell growth factor, now called interleukin-2, that permits the growth of T lymphocytes. Interleukin-2 is very important to me because I focus on the IL-2 receptor as a target for therapy for autoimmunity, malignancy, and graft rejection. IL-2 is the cardinal target of cyclosporin A, the drug so important in graft survival approaches. IL-2 has also been pivotal in studies of AIDS because it permitted the in vitro growth of lymphocytes. That in turn permitted [Dr.] Luc Montagnier to identify HIV, and the NIH groups to grow HIV and to develop assays for its cytotoxicity and its diagnosis.
Thus, if we go back nearly thirty years, we can see that we didn't know that certain infections were associated with defects in cellular immunity. We didn't have any functional assays that distinguished between antibody-producing cells (B cells), helper cells (CD4 T cells), and suppressor cells (CD8 and CD4 T cells). We did not have the ability with the antibodies to define the entry receptor utilized by HIV (CD4). We did not have the capacity to grow lymphocytes in vitro, a step required for the identification of HIV.
We are all impatient with the pace of AIDS research, but I am impressed with the unbelievable amount that has been learned in the area of clinical immunology. In part this has been due to studies of rare patients with genetic immunodeficiency diseases. I can tell a story on molecular biology as it relates to AIDS. Thirty years ago we had no restriction endonucleases; we didn't have molecular biological tools to identify components of a virus; we couldn't define whether a virus is hypermutable in the way we can identify HIV as hypermutable. The opportunity to put fragments of RNA or DNA into replicating materials for vaccine development was not available. We had had to depend, as with the polio virus, to culture the virus by getting either a dead virus by killing it with formaldehyde or getting virus that was less pathogenic but still immunologically active.
One should look not only to the 1980s and the 1990s for hope. What happened since and before the 1950s set the stage for our being able to have a chance against this plague. Without these advances, it would seem like the plague of the Dark Ages or the influenza epidemic. We are now in a position to think rationally about the AIDS problem. It is very tough problem considering that this virus, HIV, has a great capacity for mutation and thus for alternating its antigenic sites. It presents many difficulties, but I feel that so much has been learned that I'm very encouraged about the future both in terms of treatment and prevention of AIDS.
Rodrigues: Thank you very much.
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