Long-Term Survival of Skin Allografts in Mice Treated with Fractionated Total Lymphoid Irradiation

Abstract

Treatment of recipient Balb/c mice with fractionated, high-dose total lymphoid irradiation, a procedure commonly used in the therapy of human malignant lymphomas, resulted in fivefold prolongation of the survival of C57BL/Ka skin allografts despite major histocompatibility differences between the strains (H-2 d and H-2 b , respectively). Infusion of 10 7 (C57BL/Ka × Balb/c)F 1 bone marrow cells after total lymphoid irradiation further prolonged C57BL/Ka skin graft survival to more than 120 days. Total lymphoid irradiation may eventually prove useful in clinical organ transplantation.

Successful treatment of autoimmune disease in (NZB/NZW)F1 female mice by using fractionated total lymphoid irradiation.

“…TLI results in thymus-derived (T) lymphocytopenia as well as impairment of T cell functions including elimination of the in vitro responsiveness to phytohemagglutinin and the in vitro reactivity to alloantigens in a one-way mixed lymphocyte reaction. The in vivo correlate was prolonged survival of strongly histoincompatible skin and perfused heart allografts in mice and rats (13,14,17). The immunosuppressive effects of TLI in man were studied in patients who had undergone radiotherapy for Hodgkin disease.…”

“…2). At The long-lasting potent immunosuppressive effects of TLI have been well established in all animals studied so far (mice, rats, and dogs) including man (13)(14)(15)(17)(18)(19). TLI results in thymus-derived (T) lymphocytopenia as well as impairment of T cell functions including elimination of the in vitro responsiveness to phytohemagglutinin and the in vitro reactivity to alloantigens in a one-way mixed lymphocyte reaction.…”

“…TLI enabled engraftment of allogeneic bone marrow grafts without overt graft-versus-host disease and establishment of specific and permanent transplantation tolerance across major histocompatibility barriers in mice (C57BL/Ka, H -2b BALB/c, H-2 ), rats (ACI, AgB4 -Lewis, AgB'), and mongrel dogs (13,14,(17)(18)(19)(20). The effects of TLI result in immediate profound lymphocyte depletion with subsequent generation of nonspecific as well as specific suppressor T cells (21,22).…”

“…Effective lymphocytopenia with long-lasting potent immunosuppression can better be achieved by total lymphoid irradiation (TLI) consisting of fractionated daily irradiation of the major lymphoid organs with lead shielding of nonlymphoid organs (13,14). TLI is a relatively safe, noninvasive procedure routinely used for the treatment of Hodgkin disease (15).…”

Myeloablation enhances engraftment of transduced murine hematopoietic cells, but does not influence long-term expression of the transgene

“…For this reason, the search for minimal myeloablative and/or immunosuppressive treatments that allow long-term engraftment of the transduced HSC in the recipients is urgently required for the development of stem cell gene therapies for non-malignant diseases. 6,7 In the late 1970s, Slavin et al 8,9 showed that chimerism induced by infusion of allogeneic marrow after total lymphoid irradiation was associated with tolerance to skin grafts of the same donor type. More recent evidence suggests that stable mixed hematopoietic chimerisms can be induced in non-myeloablated animals receiving only immunosuppression before the infusion of allogeneic HSC [10][11][12] or by increasing the number of cells transplanted.…”