ADOPTIVE IMMUNOTHERAPY IN CANINE CHIMERAS

Chimerism and tolerance after bone marrow transplantation provide exce llent conditions for adoptive immunotherapy with T cells of the marrow donor. We studied adoptive immunotherapy in dog leukocyte antigen-ide ntical canine littermate chimeras, Mixed chimeras were produced by con ditioning treatment with total body irradiation of a dose of 10 Gy, a uniformly lethal dose in dogs, and infusion of between 1x10(8) and 2x1 0(8)/kg mononuclear marrow cells treated with absorbed antithymocyte g lobulin for inactivation of T cells. Donors were of opposite sex. Pers istent mixed chimerism was induced in six of nine dogs, chimerism was complete in one dog, and only transient in two dogs, Tolerance to dono r shin grafts was demonstrated in eight dogs, including a dog without cytogenetic evidence of chimerism, Lymphocytes of the marrow donor (be tween 3.2x10(8)/kg and 4.1x10(8)/kg) were transfused at various times after transplantation. Nontransfused dogs survived without graft-versu s-host disease (GVHD), whereas dogs transfused on days 1 and 2 and dog s transfused on days 21 and 22 developed GVHD and died. In contrast, d ogs transfused on days 61 and 62 or later survived without GVHD, Chime rism converted from mixed to complete in six of six transfused dogs an d in one of eight nontransfused dogs (P<0.005). Donor lymphocyte trans fusions 2 years and 4.5 years after transplantation induced split chim erism with lymphoid cells of donor origin and myeloid cells of host or igin in one dog and complete chimerism in the other dog. Before lympho cyte collection, donors were immunized against tetanus toxin, Seven da ys after lymphocyte transfusion, recipients were given booster injecti ons of tetanus toroid and primary immunization against diphtheria toxi n. In transfused animals, antibody titers against tetanus were demonst rated already before the booster injection. Transfused animals develop ed higher titers of antibody against tetanus and diphtheria toxin than nontransfused animals. Donor lymphocytes converted mixed chimerism in to complete chimerism without producing GVHD, when the transfusion was delayed for 2 months or later after transplantation. Transfusion of d onor lymphocytes transferred immune reactivity against tetanus toxin a nd improved reactivity against diphtheria toxin as a new antigen.