Research Activities in the Endocrine Research Lab

Dr. Robert Volpé
Wellesley Hospital, University of Toronto

For many years our laboratory has been involved in studies designed to determine the precise cause(s) of autoimmune thyroid diseases, i.e., Graves’ disease and Hashimoto’s thyroiditis. Currently, we are using two major approaches for these studies.

The first of these involves animal hosts, namely two strains of mice: the “nude” mouse and the severe combined immunodeficient (SCID) mouse.

The nude mouse has no thymus gland and therefore no T lymphocytes, and as such cannot reject human tissues (such as human thyroid tissue with autoimmune disease). In other words, the tissue can thus be grafted (xenografted) into this type of mouse. The nude mouse does have B lymphocytes and other cells which gradually kill off the human lymphocytes (immune cells). This restores the autoimmune disease tissue back to a completely normal state; not only does it look normal, but the function also returns completely to normal. These studies tell us that the thyroid cells are intrinsically normal, that the autoimmune thyroid diseases are due to an abnormal immune system acting on previously normal thyroid cells. (Incidentally, we obtain the tissue from surgical specimens, after obtaining informed consent from the patient who is undergoing surgery.)

We can then retrieve this now normalized tissue from the nude mouse and re-xenograft it into the second strain of mouse, the SCID mouse. This mouse lacks both T and B lymphocytes. Like the nude mouse, it cannot reject human thyroid tissue, but it cannot kill off human lymphocytes either. If, however, we install tissue that has already been normalized by a sojourn in the nude mouse, which has no lymphocytes anyway, that tissue will remain normal in the SCID mouse.

However, if we then introduce peripheral blood lymphocytes and other blood immune cells from the same original patient, those lymphocytes can be shown to contain “memory” cells which are drawn to the thyroid and will reproduce the disease once again, from the beginning. We are able to show by microscopic means in the tissue that the disease has returned, and the various immunological markers of the disorder also return. Cells from normal persons do not have this property.

We can manipulate the various subsets of the lymphocytes, so as to make the disease worse or better. We can delete the “suppressor T” lymphocytes, which in normal people prevent the disease – deletion makes the disease much worse. Conversely, if we add an excess of these same cells, the disease is dampened down. We have shown evidence that for each organ-specific autoimmune disease, including Graves’ disease and Hashimoto’s thyroiditis, there is a defect in the suppressor cells, which is antigen specific, and does not reflect a generalized immune abnormality. We have already published several papers dealing with these topics.

Using this model, we are now concentrating on immunotherapy in which we treat the human disease with the SCID mouse host with various molecules which interdict the immune system at different sites, in the hope that we will find a treatment that would be theoretically and practically appropriate for the human disease in the human host. We are using an agent call FK-506, which inhibits helper T lymphocytes, and which may work in this system. We are also studying an agent called gp39 which interferes with a molecule termed CD40, which in turn is important in making T lymphocytes cooperate with B lymphocytes, and which shows early promise in our system. Indeed, we have many such molecules on our list, which we will be employing in our SCID mouse system in a systematic fashion, using the techniques mentioned above. Our objective is to find a nontoxic immunotherapy which would be helpful in clinical care, particularly in exophthalmos.

We are also studying the abnormality of suppressor cells in autoimmune thyroid disease. We have early evidence that the fundamental abnormality has to do with the manner in which specific antigen activates these cells, i.e., the specific antigen does not activate the suppressor cells of patients with autoimmune thyroid diseases as much as will normal suppressor cells. Moreover, other (irrelevant) antigens will activate the suppressor cells of the autoimmune thyroid disease patients perfectly well. Thus the basic abnormality may be in the “antigen-presenting” genes, and our next studies will attempt to determine what is wrong with these genes.

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Copyright © 1996 Thyroid Foundation of Canada/La Fondation canadienne de la Thyroïde.
Reprinted from thyrobulletin, Vol. 16, No. 4, 1996.

Reviewed 2000