Rat Cardiac Allograft Survival Research Articles

The effect of cyclomunine on the in vitro responsiveness of rat and canine lymphocytes, and on rat cardiac allograft survival

The effect of cyclomunine on the in vitro responsiveness of rat and canine lymphocytes, and on rat cardiac allograft survival

SELECTIVE LYMPHOID IRRADIATION

Palladium-109-hematoporphyrin (Pd-H) is a β-emitting radioisotope with a wide safety margin between the effective and lethal doses. A single systemic injection of Pd-H localizes preferentially in the lymphoid organs and produces lymphatic and central bone marrow ablation while sparing the distal bone marrow and gastrointestinal mucosa. Selective lymphoid irradiation with Pd-H alone at one-half of the LD50 dose is not sufficient to prolong rat cardiac allograft survival without additional minimal pretreatment with antilymphocyte globulin (ALG). A sublethal dose of Pd-H (30 me/kg) with two doses of ALG (10 mg) as pretransplant treatment of Lewis recipients led to a permanent and specific acceptance of Fischer heart allografts (>450 days) and significant prolongation of ACI heart allografts. Long-term Lewis recipients of Fischer heart allografts (>150 days) demonstrated specific unresponsiveness to donor tissue by accepting a second Fischer heart allograft permanently while rejecting a third-party (ACI) heart. Lewis rats were pretreated with sublethal total-body irradiation (TBI) with and without 20 mg of ALG and received Fischer or ACI cardiac allografts. The mortality in these groups after operation was 40% (TBI alone) and 83% (TBI and ALG). Cardiac allograft survival was similar to that found in groups pretreated with Pd-H and ALG. It is concluded that selective lymphoid irradiation administered systemically is an effective, safe, and quick method of host pretreatment for prolonged allograft acceptance and may be potentially useful in induction of immunological tolerance.

Prolongation of Rat Cardiac Allograft Survival by Donor Pretreatment.Impact of Dose and Timing of Drug Administration

We investigated the effect of two variables, the time interval between drug administration and transplant removal and the dosage of the drug, on the prolongation of rat heart allograft survival via donor pretreatment. A maximal or near-maximal survival-prolonging effect was recorded when the drug was given at least 6 hours before removal of the transplant; extension of pretreatment beyond that time had relatively little effect on the outcome of the graft. A maximal survival prolonging effect was obtained with all of the test drugs, cyclophosphamide, methotrexate, hydroxyurea, busulfan and procarbazine, in doses of LD-50. The therapeutical margin was small, however, as doses of 0.5 x LD-50 and 2 X LD-50 were clearly inferior in their effect.

PROLONGATION OF RAT CARDIAC ALLOGRAFT SURVIVAL BY DONOR PRETREATMENT

We have made preliminary investigations into the effect of 33 different drugs on the survival of rat cardiac allografts, the drugs being administered to the allograft donor. All drugs were administered at LD50 i.v. to the graft donor 6 hr prior to removal of the organ. Especially effective were alkylating agents and antimetabolites. Pretreatment with cyclophosphamide, busulfan, methotrexate, azauridine, or bromodeoxyuridine prolonged the survival from 7 to more than 20 days. Pretreatment with chlorambusil, mannomustine, mannosulfan, 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea, DTC, fluoruracil, or hudroxyurea prolonged the survival to more than 14 days. Several other alkylating agents and antimetabolites prolonged the survival moderately, i.e., to approximately 10 days or more. Purine antagonists, mercaptopurine and azathioprine, were totally ineffective as were also anticancer antibiotics and vinca alkaloids. Pretreatment with procarbazine or methylprednisolone alone increased the survival only moderately, whereas pretreatment with both of these drugs together increased the survival up to 27 days.

Letter to the Editor

Abstract Sir: The article by Emerson and Thursh in the November issue of your Journal demonstrates antigen-induced trapping of immunospecific lymphocytes in the spleens of mice with a simultaneous deficiency of immunospecific lymphocytes in the peripheral lymph nodes and blood. The authors suggest that specific immunosuppression might be possibly by selectively trapping specific anti-allograft lymphocytes in the spleen and/or lymph nodes of an allograft recipient and then extirpating the spleen and/or lymph nodes by surgery or radiotherapy. This concept is exciting, for we (1) have demonstrated prolongation of Brown Norway to Lewis heterotopic rat cardiac allograft survival by performing splenectomy during a “critical” period after allografting. This “critical” period in our model included days 3 to 5 after transplantation, and prolongation could be abolished by reinfusion of a cellular suspension of viable cells from the excised spleens.