Israel Zan-Bar

The role of specific suppressor t cells in immune tolerance.

The mechanism of immune tolerance is both one of the most studied and one of the most controversial fields of immunological research. The first attempt at proposing a coherent explanation for this phenomenon is to be credited to Bumet (1959), who formulated his hypothesis as an offshoot of the clonal selection theory of acquired immunity, claiming that selective elimination of antigen-oriented clones may explain all types of specific unresponsiveness. Burnets hypothesis provides a very elegant and relatively simple explanation for the phenomenon of immune tolerance, and since it was formulated during the heyday of molecular genetics, its basically genetical orientation captured the imagination of immunologists at that time. However, his interpretation has so far found no direct experimental support, and up till now it remains mainly of a speculative nature.

Mechanisms in immune tolerance. II. Specific immunosuppression by t lymphocytes of b memory cells in mice made tolerant to hsa.

The specific suppressor cells which had been demonstrated by us in the spleens of mice tolerant to human serum albumin (HSA) could be shown to originate in the thymus of these animals. They were not depleted by passing such spleen cell suspensions on columns with an adsorbed antigen-antibody complex, a device which retains B cells, while they could be inactivated by treatment with anti θ serum and complement. These suppressor T cells were found to survive the pretreatment of their donors with hydrocortisone acetate. Nevertheless, indications were found that their precursors are apparently cortisone-sensitive since in a suitably designed experiment cortisone could be shown to interfere with tolerance induction. The suppressor cells of tolerant mice block the anamnestic response to the tolerizing antigen which can be activated after differential irradiation of tolerant animals. Analysis by means of cell transfer experiments indicated that this memory of tolerance induction was associated with a B cell population which remained functional after gamma irradiation.

Mechanisms in immune tolerance: I. A specific block of immunological memory in HSA-tolerant mice

Abstract Evidence is provided indicating that the transient immune response detected during the induction of tolerance to HSA in mice, results in immunological memory which persists in an immunosuppressed state in the tolerant animals. The mechanism which blocks this memory is antigen-specific and can be selectively inactivated by total body irradiation in the range of 650–900 R. Consequently tolerant mice, irradiated within this range and restored with normal syngeneic spleen cells, respond better to the tolerizing antigens than do similarly treated normal mice. The tolerizing block can be transmitted from “tolerant” to normal spleen cells when a mixture of both is transferred to normal irradiated recipients. Since similar inhibitory activity is also demonstrated by fresh sera of tolerant mice, it is suggested that the blocking mechanism depends on inhibitory cells which act via a humoral inhibitor.

Mechanisms in immune tolerance: III. Immunosuppression and the induction of tolerance—Synergism and antagonism

Several immunosuppressive procedures were examined for their facilitation of inducing immune tolerance to protein antigens in rabbits. Thus, gamma irradiation, 6-mercaptopurine, and cyclophosphamide treatments were found to be mutually potentiating in their effect of predisposing to the induction of tolerance. Hydrocortisone acetate, on the other hand, was found to interfere in the induction of tolerance following irradiation. An attempt is made to interpret this observation on a cellular basis.

Studies on suppressor T cells in tolerance.

(1) Evidence is provided that tolerance induced in mice to HSA depends on a suppressive mechanism which inhibits the responsiveness of potentially competent cells. (2) the suppression is apparently the function of suppressor T cells which are comparatively radiosensitive and are resistant to cortisone. (3) The cortisone resistant suppressor cells are apparently the progeny of cortisone-sensitive precursors, the differentiation of which into mature suppressors seems to be signalled by antigen. (4) The precursor lymphocytes are comparatively short functioning cells (about 14 days), while the mature suppressor T cells function for at least two months.