Discussion

Dr Weisburger: In the mid-1970s, just after the publication of Burnet's study [Burnet FM. Immunological surveillance in neoplasia. Transplant Rev 1971;7:3–25] on immune surveillance, we designed experiments in which we treated immunosuppressed animals to produce in them carcinogen-induced colon cancer. We expected these animals to develop massive cancers, but we found no difference in the orderly development of tumors by immunosuppression status [Kroes R, Berkvens JM, Weisburger JH. Immunosuppression in primary liver and colon tumor induction with N-hydroxy-N-2-fluorenylacetamide and azoxymethane. Cancer Res 1975;35:2651–6; Weisburger JH, Madison RM, Ward JM, Viguera C, Weisburger EK. Modification of diethylnitrosamine liver carcinogenesis with phenobarbital but not with immunosuppression. J Natl Cancer Inst 1975;54:1185–8]. However, when we transplanted a nonsyngeneic cancer, it would not grow in untreated animals, but it would grow in immunosuppressed rats [Prejean JD, Griswold DP, Weisburger JH. Transplantation of allogeneic tumors in rats and mice treated with azathioprine, prednisone and antilymphocyte serum. Proc Soc Exp Biol Med 1972;139:1425–8]. Thus, these experiments show that primary cancer growth and development were not affected appreciably by immune function, but transplantable cancer, which may simulate metastatic disease, was affected by immune competence.

Dr Field: As you know, cancer is not a homogeneous disease, and the immune system may play different roles in different parts of it.

Dr Milner: You said that there is no gold standard for assessing immunocompetence. Do you think there might be 4 or 5 gold standards?

Dr Field: Because the immune system is so interconnected, if you alter one component of it, you should get changes in all of the other measures. I think you have to pick the measures rationally, not because the assay is easy or because someone down the hall said, "I can measure it for you." It has to be selected based on the hypothesis that the function can be altered by the mechanism that you propose.

Dr Milner: One goal of this conference is to see whether we can begin to identify some of those biomarkers and evaluate their sensitivity.

Dr Field: The T cell is quite responsive to nutritional deficiency. In the studies done with animals in a nutritionally adequate state, when we manipulate one nutrient at a time, we get quite large changes in the control animals, not just in the diseased ones.

Dr Beck: When you talked about B cell activity not being very effective, I think often people look at IgG as an endpoint at a certain time after infection. If they look at earlier class switching or what kind of IgG is being produced, there might be some changes that people may be overlooking.

Also, I think that identifying biomarkers is most important with regard to vaccine studies. When you use a vaccine, everyone is starting at the same level; you are not dealing with different time points of exposure. You can look at specific markers for those vaccinations. You can use rhinovirus and infect people and observe their responses. I think that is more meaningful than just measuring natural killer cell activity at this time point. If the level is down 20%, does that indicate that there is an effect on the infectious process?

Dr Field: I have been leaning in that direction because it is a noninvasive approach that we could use to identify in vivo markers.

Dr Bistrian: Isn't one of the problems that the only immune tests that have been truly related generally with functionally important outcomes, such as morbidity and mortality, are delayed cutaneous hypersensitivity tests? We need to find some sensitive in vitro tests, at least one of which actually reflects a response at an early time point.

Dr Field: I agree. We need a group of healthy people who might be at risk and a measure that has been used widely and that is truly responsive to nutritional state. Many studies suggest that some of the in vitro proliferation assays actually go in that same direction.

Dr Meydani showed a set of responses: the delayed-type hypersensitivity (DTH) response, the in vivo proliferative responses, and then the production of interleukin 2. Studies that put all of those together may give us an easier in vitro test. Most in vivo measures are fairly invasive tests and can't be done in a large study. Many factors other than nutrition can modify an individual's response.

Dr Dwyer: One practical application of this is in the military, because the armed forces are concerned about maintaining good immune function for military readiness. What battery of tests would you suggest for the Canadian or American armed forces to identify factors other than dietary deficiency that affect immune response?

Dr Field: That is a difficult question, but I do think we have an opportunity with repeated testing to control for some of those variables. We cannot control whether someone catches a cold, but at least we can look for that possibility. Doing repeated measures in human populations is the only viable approach. If we can do some of the in vivo measures, whether vaccines or the DTH response, we can then take cells and study them. I am a little worried that these blood cells are not reflecting accurately the overall response of the body, especially to food, when we find that the closer we get to the gut, the more reaction we get to changes in dietary ingredients or nutrients. We need a marker that links the gut to the blood. Identifying homing mechanisms that indicate which cells are en route from the gut to different organs may, in the future, give us a better indication of the dietary response of the gut-associated immune system.