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Polly Matzinger went to the University of California, San Diego, obtaining her BS in '76 and her Ph.D. in '79. She then did post-doctoral work at the University of Cambridge, and was a scientist at the Basel Institute for Immunology before heading to the National Institutes of Health in Bethesda, Maryland.
Ghost Lab at NIAID
Polly Matzinger was a section head at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) until April 2013. Matzinger and her coworkers referred to the lab's name as the 'Ghost Lab' when listing their affiliation in papers. The nickname was given to the lab by her colleagues when Matzinger first arrived at the NIH because she spent the first nine months studying a new field (Chaos Theory) that she thought might apply to the immune system, and the lab sat empty. The formal name of her laboratory is the T-Cell Tolerance and Memory Section of the Laboratory of Cellular and Molecular Immunology. On average, the ghost lab hosts 3 post-doctoral researchers. From this knowledge pool, approximately 0-3 original research articles are published a year, including original research articles and theoretical pieces. A majority of the publications are her taken-author published works, theoretical in nature and published in very highly cited journals.
On April 1st, 2013, the NIAID administration shut down the Ghost Lab. The T-Cell Tolerance and Memory Section was incorporated into the Laboratory of Immunogenetics.
The Danger Model
The self-non-self model, the predominant model in immunology since the 1950s, began to encounter problems in the late 1980s when immunologists began to recognize that T-cells depend on other cells to pick up and then present the things to which they will respond — and that the T-cell response depends on whether the other cell (known as antigen-presenting cells) is sending activation signals to the T-cells.
In 1989, drawing on the ideas of Thomas Kuhn, Charles Janeway proposed that the old immunological paradigm had reached the limits of its usefulness—or, as he described it, the asymptote of the increase in knowledge which it had brought. Janeway argued that the innate immune system was the real gatekeeper of whether the immune system responded or did not respond. He also argued that the innate immune system used ancient pattern-recognition receptors to make these decisions - recognizing a pathogen by its unchanging characteristics.
In a 1994 article entitled "Tolerance, Danger and the Extended Family", Matzinger went several steps further by laying out the idea that antigen-presenting cells respond to "danger signals" - most notably from cells undergoing injury, stress or "bad cell death" (as opposed to apoptosis, controlled cell death). The alarm signals released by these cells let the immune system know that there is a problem requiring an immune response. She argued that T-cells and the immune response they orchestrate occurs not because of a neonatal definition of "self", as in the previous model, nor because of ancient definitions of pathogens, as in Janeway's argument, but due to a dynamic and constantly updated response to danger as defined by cellular damage.
The Danger Model is quite broad, covering topics as diverse as transplantation, maternal/fetal immunity, autoimmunity, cancer treatments, and vaccines, but Matzinger points out that the original model was designed to offer an explanation of how an immune response is triggered and how it ends, but did not offer an explanation of why the immune system responds in different ways to different situations. She has now extended the model to hypothesize that tissues not only send signals alerting the immune system to local damage and stress, but that the tissues also determine the immune response appropriate for that tissue. Before her lab was shut down by the NIAID administrators in April of 2013, her lab was working on experiments to test that hypothesis. She is currently seeking collaborations to continue the research.
The Danger Model has not won universal acceptance. Some immunologists, following Janeway's ideas more directly, believe that the immune response is mainly fueled by innate evolutionarily conserved "pattern recognition receptors" which recognize patterns expressed by microbes such as bacteria, and do not see cell death in the absence of pathogens as a primary driver of immune responses. These ideas however, do not explain how the immune system rejects transplants (most well-done transplants are not covered in bacteria), or tumors, or induce autoimmune diseases, or generate allergy and asthma.
Pattern recognition and a tissue-driven immune system
Recently, Seong and Matzinger have suggested that the "patterns" that the immune system recognizes on bacteria are not as different from the alarm signals released by damaged cells as one might have thought. They suggested that, because life evolved in water, the hydrophobic portions (Hyppos) of molecules are normally hidden in the internal parts of molecules or other structures (like membranes) and that the sudden exposure of a Hyppo is a sure sign that some injury or damage has occurred. They suggested that these are the most ancient alarm signals, that they are recognized by evolutionarily ancient systems of repair and remodeling, and that the modern immune system piggy-backed on this ancient system. Thus bacteria and other organisms may have very similar alarm systems. They describe these ancient signals as Danger-associated molecular patterns, or DAMPs.
In a 2013 article in Nature Immunology, Matzinger makes a case for what she now views as the most important implication of the Danger Model: that the tissues of the body are a large part of what drive immune response. She argues that immunologists have had overly simplistic and schematic ideas about immune response because of the limits of their assays, and that organs are likely to induce immune responses that are best-suited to defending the organ from the damage of microbes but also from the damage of the immune system itself. She also asserts that the relationship of the immune system to commensal bacteria remains poorly understood but is likely to be important.
Matzinger argues that the idea of DAMPs may explain why Toll-like receptors seem to respond both to external and endogenous signals (while acknowledging controversy over this issue). By emphasizing her theory that the tissues drive the nature of the immune response (i.e., the "what type" rather than the "whether" of immune response), Matzinger describes a dynamic immune system with complex webs of signalling, rather than an immune system that can be explained by a simple and easily reducible set of molecular signals that initiate response, or by a small set of cells (e.g., "regulatory" T cells) which shut it down.
Challenges to Matzinger's theories
There is now a growing body of work on "regulatory T-cells" which argues that immune activity is stopped by a special subset of T-cells. These ideas challenge several of the key specifics of Matzinger's model. Matzinger argues that these cells are mis-interpreted because their functions have not been explored enough. To date (with rare exceptions) these cells have been tested almost exclusively for their ability to suppress highly inflammatory immune response types. The exceptions are illustrative in that they show that regulatory T cells can also act as helper T cells for immune responses in the gut and mucosal tissue. Matzinger argues that their function is to maintain the right kinds of immune responses in the right places, and that they are controlled by signals from the tissues that they protect.
A student sitting in an immunology class today will likely hear many phrases coined by Matzinger, such as "professional antigen-presenting-cell", "danger signal", or "DAMPs" (damage associated molecular patterns), but will often hear them in the framework of a self-non-self explanation of immunity. Other immunologists have often adapted parts of Matzinger's ideas without adopting the Danger Model as a theoretical framework.
Indeed, in an era of increasingly detailed molecular work, many immunologists simply avoid constructing an alternative broad theory of immune function. One immunologist believes that the immune system is not a single system at all, and is instead a set of mechanisms "cobbled together" by evolution. If this is true, no single theory can explain the function of the system as a whole. For both of these reasons, Matzinger has had to defend her larger theory, but also has had to defend the value of grand theory itself. She argues that, without a theoretical framework on which to hang the data, much will be missed.
Past and current work with dogs
In one of her first publications, she appeared to have a dog as a coauthor for a paper for the Journal of Experimental Medicine. As Ted Anton described the decision in his book Bold Science, "Refusing to write in the usual scientific passive voice ('steps were taken') and too insecure to write in the first person ('I took the steps'), she instead invented [a] coauthor": her Afghan Hound, Galadriel Mirkwood. Once discovered, papers on which she was a major author were then barred from the journal until the editor died and was replaced by another.
Although no dogs have been coauthors of any of her recent papers, she is an avid sheepdog trainer, and, with her two Border Collies, Charlie and Lily, was on the team that represented the United States at the 2005 World Sheepdog Finals in Tullamore, Ireland. She is one of the featured scientists (along with one of her sheepdogs) in the 1995 science documentary Death by Design/The Life and Times of Life and Times.
- Matzinger, P. and Mirkwood, G. (1978). In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type. Journal of Experimental Medicine, 148, 84-92.
- Lassila, O., Vainio, O. and Matzinger, P. (1988). Can B cells turn on virgin T cells? Nature, 334, 253-255. (the article in which "professional antigen presenting cells" were first named)
- Fuchs, E., and Matzinger, P. B. (1992). B cells turn off virgin but not memory T cells. Science, 258, 1156-1159.
- Matzinger, P. (1994). Tolerance, Danger, and the Extended Family. Ann. Reviews of Immunology, 12, 991-1045.
- Ridge, J.P., Fuchs, E., and Matzinger, P. (1996). Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science, 271, 1723-1726.
- Ridge, J.P., Di Rosa, F. and Matzinger, P. (1998). A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T- killer cell. Nature, 393, 474-478.
- Gallucci, S., Lolkema, M. and Matzinger, P. (1999). Natural adjuvants: Endogenous activators of dendritic cells. Nature Medicine, 5, 1249-1255.
- Matzinger P. (2002). The Danger Model: A Renewed Sense of Self. Science, 296, 301-305.
- Seong, S. and Matzinger, P. (2004). Hydrophobicity, an ancient Damage-associated Molecular Pattern that initiates Innate Immune Responses. Nature Rev. Imm., 4, 469-78.
- Matzinger, P. (2007). Friendly and dangerous signals: is the tissue in control? Nature Immunol,8,11-13.
- Matzinger, P and Kamala T. (2011) Tissue-based class control: the other side of tolerance. Nature Reviews Immunology 11:221-30 
- Ainhoa Perez-Diez, Nathalie T. Joncker, Kyungho Choi, William F. N. Chan, Colin C. Anderson, Olivier Lantz, and Polly Matzinger. (2007). CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood, 109, 5346-5354.5346]
- Immunity: the inside story. Matzinger P and André Trauneker (1986) (video, 13 min). Award winning animated film for lay people describing the events involved in clearing an influenza infection. Translated into German, French, Spanish. Hoffmann-La Roche studio, Basel, Switzerland
- A quick look at tissue rejection. Matzinger P. (1991) (Video, 2 min). Animated film for lay people describing the events that result in rejection of a skin graft. Commissioned by the National Association of Science Writers for a meeting of television producers. NIH special events department and Capitol Studios
- Death by Design/The Life and Times of Life and Times. Peter Friedman and Jean-François Brunet (1995) (Film, 73 minutes). Award winning film on apoptotic cell death that features the work of six scientists. P Matzinger, R Levy-Montalcini, M Raff, P Goldstein, KM Debatin, R Horowitz among others
- Turned on by Danger. Michael Mosley (1997) (Film, 60 minutes). A BBC Horizon program made for public television featuring and delineating the Danger model.
- Microbe Invasion. David Green (2001) (Film, 60 minutes). A program describing the interrelationship between human bodies and the multitude of organisms that live on and within them. The film features the Danger model as the model of immunity that best allows for symbiotic relationships within the body. The Learning Channel
- DREIFUS, CLAUDIA (June 16, 1998). "A Conversation With Polly Matzinger; Blazing an Unconventional Trail to a New Theory of Immunity". Nytimes.com. Retrieved 19 Jan 2015.
- "Polly Matzinger, Ph.D., T-Cell Tolerance and Memory Section, Laboratory of Immunogenetics, NIAID, NIH". .niaid.nih.gov. 2013-03-27. Retrieved 2013-08-01.
- "Home - PubMed - NCBI". Ncbi.nlm.nih.gov. 2013-03-25. Retrieved 2013-08-01.
- "Friendly and dangerous signals: is the tissue in...". Ncbi.nlm.nih.gov. 2013-03-25. Retrieved 2013-08-01.
- Russell E. Vance2 (2000-08-15). "Cutting Edge Commentary: A Copernican Revolution? Doubts About the Danger Theory". Jimmunol.org. Retrieved 2013-08-01.
- Polly Matzinger and Galadriel Mirkwood. "In A Fully H-2 Incompatible Chimera, T Cells of Donor Origin Can Respond to Minor Histocompatibility Antigens in Association With Either Donor or Host H-2 Type" (PDF). Jem.org. Retrieved 2013-10-17.
- Anton, Ted. Bold Science: Seven Scientists Who Are Changing Our World. New York: WH Freeman, 2000.
- "Death by Design: Where Parallel Worlds Meet (1997) : Full Cast & Crew". IMDb.com. Retrieved 2013-10-17.
- "Death By Design". Strange Attractions. Retrieved 2013-10-17.
- Matzinger's farm homepage, (Ambling Brook Farm)
- Matzinger profile in the British Journal of Ophthalmology
- "My Scientific Sins" item in The Scientist magazine
- Matzinger profile in Arthritis Today
- Death by Design/The Life and Times of Life and Times at the Internet Movie Database
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