A Sampling of Denver Immunology History and Highlights
David W. Talmage……clonal selection
One of the first contemporary immunologists in the University of Colorado academic community, David W. Talmage made significant contributions to the clonal selection theory. Together with Australian immunologist Frank Macfarlane Burnet, he formulated the clonal selection theory.
Talmage, in a review early in 1957 (Talmage, D. W. (1957) Allergy and immunology. Annual Reviews of Medicine 8, 239-256.) wrote: " . . . it is tempting to consider that one of the multiplying units in the antibody response is the cell itself. According to this hypothesis, only those cells are selected for multiplication whose synthesized product has affinity for the antigen injected. This would have the disadvantage of requiring a different species of cell for each species of protein produced, but would not increase the total amount of configurational information required on the hereditary process." One can argue about the definition of the clonal selection theory, however even though Talmage did not use the phrase "clonal selection", it is clear that it was more than “hint” or “brief suggestion”.
Henry Claman…..T cell-B cell collaboration
Henry N. Claman, like his mother, father, and grandfather, decided to become a physician. After medical school he joined the US Army and while stationed at Fort Meade in Maryland was given orders to start an allergy clinic. He worked as an allergist at Johns Hopkins, and at the end of his obligatory two years he joined the laboratory of Dr David W. Talmage at the University of Colorado Medical School in Denver.
In 1967, Henry Claman provided the first evidence that cells originating from the thymus and bone marrow somehow collaborate in generation of antibody responses: he essentially delineated the separate and complementary roles for T cells and B cells. In addition, Dr. Claman studied the effects of corticosteroids on lymphoid cells, as well as the basis of tolerance, the immunology of pregnancy, “suppressor” T cells (predecessor of T regulatory cells), chronic graft-versus-host disease, and mast cells in scleroderma.
Kimishige Ishizaka.…IgE
Kimishige Ishizaka came to Denver in 1962 from Johns Hopkins and worked at the Children’s Asthma Research Institute and Hospital that later became part of what is now National Jewish Health. Kimi and his wife Teruko were interested in the basis of anaphylaxis. Skin sensitizing antibodies or anaphylactic antibodies were at the time referred to as "reagins". It was shown by Prausnitz and Kustner in 1921 that serum from allergic patients, when injected intradermally into non-allergic patients would cause and allergic reaction to the antigens to which the serum donor was allergic (caused by regains). In the early 1960’s three of the immunoglobulin isotypes were known: 7S-immunoglobulin (IgG), 19S-immunoglobulin (IgM) and β2A or γ1A globulin (IgA). At that time Kimi and Terry and a post doc named Tomio Tada first claimed that they had found a new reagin that belonged to the IgA class of immunoglobulin. But there were several observations that led them to question whether this “ reaginic” activity was truly from IgA. Thus they developed an improved multistep procedure for the fractionation of sera from ragweed-sensitive persons, and produced a highly purified reagin fraction. This work showed that reagin was not, after all, of the IgA class but was distinct from the three then known human immunoglobulin classes IgG, IgM and IgA. The allergenic constituent ("antigen E") of ragweed pollen extract could be detected in the gamma 1-globulin precipitin band formed on interaction of the rabbit antiserum. In 1967 they isolated and discovered “ γE” as they proposed or as it is known today, IgE .
Peter Henson……Lung inflammation and its resolution
Peter Henson was recruited to National Jewish in 1977 from Scripps Research Institute where his research focused on immunopathology of skin, kidney and lung. During his tenure at Scripps Dr. Henson discovered a phospholipid mediator, PAF (platelet activating factor) and demonstrated that release of mediators from inflammatory cells involved active, controllable secretory processes (contrary to what was believed at the time: that it was a passive release of constituents following cell lysis). At National Jewish Dr. Henson served as Executive Vice President for Academic Affairs stepping down to pursue his research fulltime in 1997. His work is now focused on mechanisms of resolution of pulmonary inflammation. Dr. Henson’s lab was the first to demonstrate that apoptotic cells are removed by phagocytes and that phosphatidylserine exposed on the surface of the dying cells is recognized by macrophages and other cells as a signal for ingestion as well as an agent for silent (i.e. immunosuppressive and inflammosuppressive) cell deletion.
Howard Grey …..Antigenic peptide interaction with MHC
In 1970 Dr. Howard Grey was recruited to National Jewish Hospital from the Scripps Institute. He served 1978 to 1988 as Head of the Basic Immunology Division in the Department of Medicine. During this period Dr. Grey's research focused on defining the molecular and cellular mechanisms of antigen recognition by T cells. His most important work was the demonstration that in antigen presenting cells antigen derived peptides become associated with MHC molecules, thereby generating composite epitopes recognized by T cells.
John Kappler and Philippa Marrack……Discovery of the T cell antigen receptor
John Kappler and “Pippa” Marrack were postdoctoral fellows in the laboratory of Richard Dutton at the University of California, San Diego. In 1973 they moved as a team to faculty positions at the University of Rochester. In 1979, they were recruited by Howard Grey to National Jewish and the University of Colorado. They are recognized for their collective body of work related to various aspects of T cell specificity and biology. Perhaps most notable is their original development in 1983 of antibodies that could differentiate among T cell clones by virtue of recognition of antigen receptors (TCR), and use of these to define the structure and function aspects of the TCR. In 1987, they provided the first evidence that autoreactive T cells are negatively selected. They showed in mice that if a T cell receptor binds self antigen in the thymus, the T cell dies. Cells that recognize foreign antigen and do not bind self-antigen mature and leave the thymus. With collaborators, Kappler and Marrack also showed that certain bacterial toxins, so-called “superantigens” cause toxic shock syndrome and food poisoning by a process involving polyclonal activation of T cells.
John Cambier…..Discovery of B cell antigen receptor transducers and mode of signaling
John Cambier was recruited to National Jewish from Duke University in 1983. In 1999 he became the first permanent chair of the Department of Immunology. Dr. Cambier’s research is focused on transmembrane signaling mechanisms underlying different cell fate decisions in the immune system. His laboratory was the first to describe the signal transducers utilized by B cell antigen receptors and their transduction of signals via onboard tyrosines and associated tyrosine kinases. He also discovered that inhibitory receptors mediate their function by recruitment and activation of tyrosine and lipid phosphatases, establishing a paradigm applicable to the >100 inhibitory receptors described to date. Finally his work has established that most autoreactive B cell are silenced by anergy, a condition wherein cells populate peripheral lymphoid organs but remain unresponsive to antigen, and thus do not participate in immune responses. Current studies address the unique signaling pathways that maintain this unresponsiveness and its failure in autoimmunity.
David Nemazee…..Immune tolerance by B cell antigen receptor editing
David Nemazee was recruited to National Jewish from the Basel Institute for Immunology in 1988. While on the faculty he focused on silencing of autoreactive during B cell development. During maturation in the bone marrow, B-cells are tested for interaction with self antigens and those that are autoreactive are silenced by one of three mechanisms known as receptor editing, clonal deletion or anergy. In 1993 he discovered receptor editing, reporting that signaling through an autoreactive antigen receptor can promote further immunoglobulin gene rearrangements, leading to replacement of the offensive specificity with an 'innocuous' one, thereby eliminating the autoreactivity of the cell without eliminating the cell itself.
Abraham “Avi” Kupfer….Discovery of the immunological synapse
Avi Kupfer joined our faculty after completing postdoctoral studies in the laboratory of John Singer at UCSD. In 1998, Avi reported the original description of an important structure known as the immunological synapse or super-molecular activation complex (SMAC). This is structure that forms at the point of contract between an antigen presenting cell and a T lymphocyte during T cell recognition of antigen MHC. Key molecules shown by Dr. Kupfer to occur in the synapse are the TCR and MHC as well as LFA-1, ICAM-1, CD28, and CD80/CD86. The structure is composed of concentric rings, the C-SMAC, the P-SMAC, and the D-SMAC each containing different combinations of molecules.
