Immunosuppression and induction of tolerance by fractionated total lymphoid irradiation
Morecki, S.; Or, R.; Weshler, Z.; Slavin, S.
Harefuah 109(7-8): 165-169
1985
ISSN/ISBN: 0017-7768 PMID: 3935551 Document Number: 262557
Fractionated total lymphoid irradiation (TLI) is a relatively safe, recently introduced radiotherapy technique for immunosuppression and induction of tolerance. Selective radiation is directed to the lymphoid organs while the nonlymphoid organs are shielded. The radiation is divided into daily fractions of well-tolerated doses (100-200 rads) resulting in minimal side effects but reaching a high cumulative dose. The immunosuppressive effects were exploited in the successful treatment of auto-immune manifestations in experimental models and in a pilot study of patients with auto-immune disorders. The post-TLI immunosuppressed state enabled permanent allogeneic engraftment of bone marrow cells. Skin grafts taken from the bone marrow donor strain were permanently accepted, but from an unrelated donor were promptly rejected. Documentation of long-term allograft survival was further extended in rat, dog and monkey. TLI-induced engraftment of allogeneic bone marrow cells was employed to achieve a graft-versus-leukemia effect in mice carrying a B-cell leukemia and for enzyme replacement therapy in .beta.-glucuronidase-deficient mice. TLI was effective in inducing specific tolerance to soluble antigen without damaging the antibody response to unrelated antigens. Suppressor cells induced after TLI could not be ascribed to either the lymphoid or macrophage lineages nor to NK cells. Recent studies indicate that tolerance in TLI-treated mice is mediated by functional clonal deletion of alloreactive cells, rather than by active cellular suppression. Pilot clinical use of TLI in man has been initiated in kidney transplantation and as conditioning for bone marrow transplantation in aplastic anemia. Currently, attention is directed at improving protocols in order to ensure maximum success.