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Hildenbrand G pg. 1 Practice of Gerson’s diet therapy in neoplastic diseases: A tissue-centric nutritional immunotherapy that anticipated Matzinger’s Danger Model with its tissue-based effector class control Gar Hildenbrand Dir Epidemiology - Gerson Research Organization Dir Research – Centro Hospitalario Internacional del Pacifico SA Lecture and PowerPoint presentation to the American Academy of Anti-Aging Medicine Fellowship in Integrative Cancer Therapy: Module II June 25, 2011 Las Vegas, Nevada Fellowship Dir: Mark Rosenberg, M.D. Hildenbrand G pg. 2 Gerson Research Organization 7807 Artesian Rd San Diego CA 92127 http://www.gerson-research.org garhildenbrand.com email: [email protected] Hildenbrand G pg. 3 Practice of Gerson’s diet therapy in neoplastic diseases: A tissue-centric nutritional immunotherapy that anticipated Matzinger’s Danger Model with its tissue-based effector class control Gar Hildenbrand Dir Epidemiology - Gerson Research Organization Dir Research – Centro Hospitalario Internacional del Pacifico SA Lecture and PowerPoint presentation to the American Academy of Anti-Aging Medicine Fellowship in Integrative Cancer Therapy: Module II June 25, 2011 Las Vegas, Nevada Fellowship Dir: Mark Rosenberg, M.D. Abstract Gerson labored alone at first, and later with extraordinary support, to develop a nutritional immunotherapeutic approach to tuberculosis. This disciplined clinical investigation led to some unconventional ways of conceiving of and monitoring the immune response of tissues per se, and manipulating them through diet. Gerson translated this new approach into a method of cancer management. Matzinger’s Danger Model predicts that an improvement in tissue function will lead to Garmore Hildenbrand: effective effector class control. Lecture Gar Hildenbrand: What if the immune system is not a surveillance army of specialized lymphocytes with advanced knowledge of self and not-self? What if Charlie Janeway was wrong? What if the tissues, themselves, initiate, tailor, am- plify and signal the completion of immune responses? What if T-regulatory cells express helper functions according to instructions from the tissues? What if we’re misidentifying T-regulatory cells due to the culture media and the assays we are using in our experiments? What if we are missing the tissue responses that govern the class of effector? Christeene and I had dinner and too much wine a couple of months back with Polly Matzinger, who’s the Chief of the T- cell Tolerance Memory Section of the Immunology Lab at NIAID and a co-conspirator along with Steve Groft, the Direc- tor of the Office of Rare Diseases Research, to go back in on the Coley question, to start with large animals and live streptococcus pyogenes infections, because the large animals, like Arabian horses, can get melanomas, for example; dogs can get sarcomas, that are much, much closer than murine models to human beings. And really, if we want to know what makes tumors clear, we need to know what aspect of immunity is evoked. And of course, at this point, “what aspect of immunity” becomes a much larger question. Hildenbrand G pg. 4 I’m going to do what Dr. Pauling always did in his lectures, and he Students generally learn that the immune system told us that we should do this. I’m going to read what is up on the matches the effector class to the pathogen that it is fighting (for example, making IgE against worms, screen instead of say something else, which always drove him crazy and cytotoxic T lymphocytes (CTL) against viruses when a speaker would do that. and intracellular bacteria). But it is not easy to see how the immune system could discriminate Gerson labored alone at first — we’re talking about Max Gerson between worms, viruses or intracellular bacteria, as T cell receptors bind peptide-MHC complexes, B back in the 19-teens and twenties, in Germany, in Bielefeld — later cell receptors bind small epitopes on proteins, with extraordinary support, to develop a nutritional immunotherapeu- carbohydrates and lipids that are present in most tic approach to tuberculosis. This disciplined clinical investigation led living organisms; ... Slide 3 to some unconventional ways of conceiving of and monitoring the immune response of tissues per se, and manipulating them through Matzinger PC, Kamala T. Tissue-based class control: the other side of tolerance. Nature Reviews Immunology 2011;11:221-230 diet. Gerson translated this new approach into a method of cancer management — I could say via tuberculosis, which is where he started — Matzinger’s Danger Model predicts that an improvement (cont) and the ‘innate’ receptors, such as the Toll- in tissue function will lead to more effective effector class control. like receptors (TLRs) and NOD-like receptors (NLRs) are so promiscuous that they don’t Sounds interesting. distinguish between ligands from different phyla, or between pathogen-derived and self-derived signals From a February publication of Polly Matzinger, in the February is- ... So, what controls the effector class of an sue of Nature Reviews Immunology, this year, Students generally immune response? The idea that it might be the tissues, rather than the immune system, has grown learn that the immune system matches the effector class to the slowly over the 13 years that we have been pathogen — matches the effector class to the pathogen — that it is studying immunity from the perspective of the fighting (for example, making IgE against worms, and cytotoxic T danger model. Slide 4 lymphocytes (CTL) against viruses and intracellular bacteria). But it is not easy to see how the immune system could discriminate be- Matzinger PC, Kamala T. Tissue-based class control: the other side of tolerance. Nature Reviews Immunology 2011;11:221-230 tween worms, viruses or intracellular bacteria, as T cell receptors bind peptide-MHC complexes, B cell receptors bind small epitopes on proteins, carbohydrates and lipids that are present in most living (cont) Initially, the model did not offer any clues as organisms; and the ‘innate’ receptors, such as the Toll-like receptors to how one effector class might be chosen over another, as it was designed to cover only the (TLRs) and NOD-like receptors (NLRs) are so promiscuous that they immune system’s first decision (whether to respond don’t distinguish between ligands from different phyla, or between or not). It proposed that perturbed tissues initiate pathogen-derived and self-derived signals ... So, what controls the immune responses by sending alarm signals that activate local antigen-presenting cells (APCs), effector class of an immune response? The idea that it might be the whereas healthy tissues display their own antigens tissues, rather than the immune system, has grown slowly over the or allow ‘resting’ APCs to display those antigens to 13 years that we have been studying immunity from the perspective induce peripheral tolerance... of the danger model. Slide 5 Continuing ... Initially, the model did not offer any clues as to how Matzinger PC, Kamala T. Tissue-based class control: the other side of tolerance. Nature Reviews Immunology 2011;11:221-230 one effector class might be chosen over another, as it was designed to cover only the immune system’s first decision (whether to respond or not). It proposed that perturbed tissues initiate immune responses (cont) In effect, this model suggested that turning by sending alarm signals that activate local antigen-presenting cells immune responses on or off was the prerogative of (APCs), whereas healthy tissues display their own antigens or allow the tissues. It takes only a small step to suggest that tissues may also control the effector class, ‘resting’ APCs to display those antigens to induce peripheral toler- such that the class of an immune response is ance. In effect, this model suggested that turning immune responses tailored to the tissue in which it occurs, rather than on or off was the prerogative of the tissues. It takes only a small step to the invading pathogen. to suggest that tissues may also control the effector class, such that the class of an immune response is tailored to the tissue in which it occurs, rather than to the invading pathogen. Slide 6 Just think about it, if you had a T-cell response in your gut, or your Matzinger PC, Kamala T. Tissue-based class control: the other side of tolerance. Nature Reviews Immunology 2011;11:221-230 brain, or your eye, you would lose those structures and organs, be- Hildenbrand G pg. 5 cause it is such a destructive response. So an Ig response is re- quired in those tissues. How in the world could the immune system In fact, we should perhaps redefine the immune know to respond that way? system to include every tissue in the body. Again with Polly ... In fact, we should perhaps redefine the immune system to include every tissue in the body. Slide 7 This is “girlfriend,” here. Polly is 73 years old. She started out as a cocktail waitress in the Playboy Lounge where some scientists were Matzinger PC, Kamala T. Tissue-based class control: the other side of tolerance. Nature Reviews talking and she overheard them. They were talking about Immunology 2011;11:221-230 biomimicry and she asked, as she was serving the cock- tails, “Why doesn’t anything mimic a skunk?” To which, to Slide 8 her delight, the scientists responded by engaging her in a Polly Matzinger (and disciple) conversation and, over a period of time, one of them be- came convinced that she had a gift and talked her into pursuing studies in the sciences. And as I said, she is now the long-term head of the Ghost Lab, so-called be- cause for the first nine months there was no one there, because Polly had gotten it into her head that string the- ory might be important.

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