Immunotoxicology: A Tribute to Dr. Vera Stejskal

This is a story about immunotoxicology, the field of immunity, as it relates to the exposure to toxic substances. And my extraordinary luck in meeting one of the developers of this field, Dr. Vera Stigshall. In 1994 I had the privilege of being invited to Sweden to give a presentation and was introduced to Dr. Stigshall, who, who at the time was the head of the immunological laboratory in immunotoxicology for the well known and highly valued Ostra pharmaceutical company in Sweden, later to become AstraZeneca. Dr. Stegshall had developed an extraordinary technology for evaluating the influence of various substances on immunological function by lymphocyte testing, later to be called the Melisa test. And I had the privilege of having long discussions with Dr. Stegshall about this technology and how it could be used to assess low level toxins and the effect that it had on our immune system. Unfortunately, Dr. Stegshall passed away last year. She had an incredible years of contribution to the field and I want to take a moment just to review what she left us with, with the concept of the Melisa test, the test of her development. But to properly understand how she developed this test is to really understand her unique contributions to the field through her work at Ostra. She was an immunologist by training from the Czech Republic, then relocated to Sweden where she was at the university and studying immunological function, developing new assay methods and was then hired on at Astra to be an immunologist. Having to confront then early on one of the significant issues of challenge for the drug company that was developing at the first time an antacid material that was called Prilosec. Many of you are familiar with this Omeprazole, that would be the first drug, an H2 blocking drug that would be an antacid to treat esophageal reflux and acid reflux conditions. This drug was to become later a several billion dollar a year revenue generator for the drug company, making it an internationally famous drug company. So it's on one single technology and discovery that this company vaunted itself forward internationally. But they came to a very big crossroads in the approval of this drug in the United States because of a toxic effect they had in one of their pre clinical studies in dogs. And the drug was going to be held up for approval in the United States, which would basically have killed it in their financial planning and modeling. Knowing that this was going to be the major market for the drug, they called on Dr. Stegshall to find out if she could identify why this drug had been toxic in this animal model that had prevented its approval. And put her immune knowledge of toxicology to work to develop then an application for a test that she had been working on for some time, this lymphocyte stimulation test, later to be called the MELISA test, under her registered name, to evaluate then how this drug could have produced this problem of necrotizing enterocolitis in the dogs. In examining this, she, through her detective work, found out that it only was occurring in a certain specie of dog and it only occurred in dogs that had been in that specie pre treated with an anti worming medicine. And it was the interaction of the anti worming medicine with that specific genotype of that dog that produced that toxic effect when administered the drug omeprazole. She later showed that if dogs were not worm infested and had not been pre treated with anti worming medication, that they were completely tolerant to the drug omeprazole and there was no toxic effect. And in fact, that work ultimately when presented to the US fda, led to the approval of drug and ultimately billions of dollars of revenue to the company. The company was so excited about that that they awarded Dr. Stegshall with a laboratory of her own and an annual award where she could do any kind of research that she wanted. She made the decision that she was going to pursue then this toxicological assay looking at low level toxins in the environment, particularly metals, because she was of the belief that these so called inert metals, palladium, platinum, nickel, things that were being used in implant materials in sur were not as benign as they had been thought to be. And maybe in some individuals, based upon their genotype and their immunological uniqueness, could produce immunotoxicology or toxic effects. And so she put her new test to work in trying to study individual uniqueness in response to metals, only to open up the field of metal toxicology that had never been a field prior to her contributions. And in fact, if we go back to look at some of her early publications, we find that this kind of detective story that she was developing around toxicology was really built around some fundamental understanding of the cytotoxic effects and lymphocytes of various foreign substances. And in fact, I went back to 1973 in one of her first publications, cytotoxic effects of activated lymphocytes and their supernatants, showing in fact that white cells could be used as markers both ex vivo and in vivo for evaluating toxicology at very low levels. Of activity or response or meaning very high levels of sensitivity. In fact, There are some 50 or more publications that Dr. Steckshall developed over the next years to come around this technology. Ultimately with a more recent publication on the identification of metal sensitization in sarcoid like metal exposed patients by her Melisa lymphocyte proliferation assay, showing that these inert metals were not as inert as had been previously believed and in fact in some individuals at part per billion levels could produce immunological effects. It was the birthing of this particular discipline of metal toxicology that ultimately gave rise to a whole foundation that has now been formed. The Council for Nutrition and Environmental Medicine has this subject chapter looking at metal toxicology. This is all a legacy to the contributions that were made by Dr. Stevshall over her years of service. And it's still interesting to me that today we are not yet completely understanding in medicine the contributions that she's made through these multiple studies and multiple animal and human intervention trials looking at low level metal toxicology and the effect on immune function. So this is a moment to shout out to Dr. Stegshall. I had the privilege of talking with her at length, getting to know her, having dinners to discuss science with her over the years. Remarkable personality, a tough spirit, A person that was not easy to give up and continue to forge forward in her ideas. It really has created a whole new discipline in immunology, the metal toxicology, immunotoxicology discipline. And I think today we need to be very mindful of this work as it relates to certain conditions of neurological or immunological origin that are related to this low level personalized adverse response to metals. Not just mercury, but palladium, platinum, nickel, elements that were previously thought to be completely inert, that in individual cases of sensitivity could produce immunological defects indicating things like autoimmune disease. Thank you Dr. Stengshaw, for all your incredible contributions. We'll miss you.