David A. Blumenstock

The first transplantation of the lung in a human revisited

The first homotransplantation of the lung in a human was performed in early 1963, thirty years ago. It is the purpose of this review to evaluate the significance of this event and to determine its effects on the further development of lung transplantation.

FUNCTIONING HOMOGRAFTS OF THE LUNG IN DOGS

A lung autograft in the dog can survive indefinitely and perform almost normal pulmonary function.lS2 A lung homograft is destroyed in six days. The first evidence of rejection, the appearance of a few perivascular round cells, occurs two days after transplantation. Moderate pulmonary edema and increasing concentrations of lymphocytes are seen at four days. Hemorrhagic necrosis of the transplanted lung is found after the sixth post-transplant day unless measures are taken to alter the rejection response. This report describes three methods of altering the immune response to homografts of the lung which allow prolonged graft survival.

Immunologic, morphologic, and functional evaluation of long-term-surviving beagle lung allograft recipients treated with lethal total-body irradiation, autologous bone marrow, and methotrexate

Immunologic, morphologic, and functional evaluations were performed in beagle dogs with single lung allografts surviving 3–13 years after transplantation. Immunosuppressive treatment included lethal totalbody irradiation, autologous bone marrow reconstitution, and three doses of methotrexate. Three beagle recipients with full DLA-haplotype-matched grafts and five recipients with one-haplotype-mismatched grafts were studied. Evidence of rejection—i.e., infiltrates on chest roentgenograms, hypoperfusion on radionuclide lung scans, and histopathologic changes—were absent in the matched recipients and in three of the five mismatched recipients. Two of the mismatched recipients had decreased perfusion to their allografted lungs, and open-lung biopsy specimens revealed diffuse fibrotic blood vessels with narrowed lumina but no other abnormalities. Decreased fractional blood flow to the lung allograft of the five one-haplotype-mismatched recipients was correlated (r=-0.92) with the level of donor-specific cytolytic lymphocyte activity generated in mixed lymphocyte cultures (MLC). In contrast, the level of proliferative activity in donor-specific MLC did not correlate well with graft function. These findings suggest that the mechanism of tolerance to these lung allografts (with particular regard to vascular integrity) involves attenuation of the response against major histocompatibility complex (MHC) class I alloantigen since the induction of cytolytic T lymphocytes in MLC is directed primarily against these molecules. Though all of the mismatched recipients had the ability to react against MHC class II alloantigens in vitro (as demonstrated by proliferative responses in MLC), in vivo responses to class II gene products may not occur because of the lack of expression of these molecules on long-term surviving grafts.

The Lung and Other Organs Transplantation Of The Lung

The present status of lung transplantation is reviewed. The following statements can be made.Techniques of autotransplantation and allotransplantation have been developed for animals and man.Autotransplants of the lung can function indefinitely.Bilateral autotransplantation can be tolerated with an interval of as little as one week between the operative procedures. Such transplants can support normal activity indefinitely.A variety of immunosuppressive programs can prolong survival and function of allotransplants of lung. Pulmonary function deteriorates when acute or chronic rejection occurs.Successful unilateral and bilateral replantation of the lung have been reported in man. To date, no successful allotransplants have been recorded.

LEUKOKINETICS IN DOGS GIVEN SUPRALETHAL IRRADIATION WITH OR WITHOUT A GRAFT OF MARROW

The purpose of this communication is to describe some of our observations on leukokinetics in dogs given large doses of whole-body irradiation and subjected to cross-circulation or marrow grafting. The homotransplantation problems associated with marrow grafting and the complications associated with immunologically competent cells in the peripheral blood have been described in detail elsewhere. l a 2 At this conference it is necessary only to acknowledge the basic information provided by leukapheresi~,3*~ by cross-circulation,s-B and by radioactive tracers.9-11

LUNG TRANSPLANTATION IN THE DOG

Juvenelle successfully reimplanted the left lung in a dog in 1951.*,2 Neptune, Weller, and Bailey demonstrated the modem technique of homotransplantation of the lung in 1953.3 Since then there have been several reports of homotransp1,antation of the lung in animals and The preliminary results of our attempts to extend survival of homotransplants of the lung were presented in 1962.1° An evaluation of the survivors of this series of 45 homotransplantations is the subject of this report. Attention is directed primarily to those animals surviving more than five months.

Late pulmonary function after reimplantation and allotransplantation of the lung in dogs.

SUMMARY Distribution of pulmonary ventilation and perfusion and pulmonary gas exchange were studied in 2 dogs surviving 4 years after bilateral reimplantation and 4 dogs surviving 13-25 months after unilateral allotransplantation of the lung. These studies showed variable degrees of pulmonary dysfunction in all animals but significant levels of function could be demonstrated in all lungs tested. Gas exchange was best when reduction of ventilation was matched by reduction in perfusion. Animals were observed to survive and appear normal with bilaterally reimplanted lungs.

TREATMENT BY TRANSFUSION OF SEVERE GENERAL RADIATION INJURY IN DOGS.

The effects of transfusion of fresh whole blood were observed in 55 dogs exposed to 1,250 ± 100 r of continuous total body gamma radiation. Seven controls received the same basic care, fluids and antibiotics, but no transfusions. The amount of blood administered ranged from 100–150 ml in daily infusions through exchanges of seven liters or more repeated once or twice. Transfusion increased survival time but hazards were apparent. The anesthesia and surgical procedures required for the larger exchanges of blood led to complicating infections. Large amounts of fresh unirradiated blood induced early return of hematopoiesis apparently by implantation of cells present in the blood administered, but jaundice and serious liver injury also occurred, perhaps as a reaction of foreiga cells against their host. Best results were obtained by frequent non‐traumatic administration of small amounts of blood, roughly equivalent to one‐tenth the dogs blood volume daily. There were two long term survivors. One received irradiated blood and the other received blood from a litter‐mate.

Pulmonary function of haplotype-matched and mismatched allografts in dogs treated with total-body irradiation, autologous marrow transplantation, methotrexate, and donor blood.

Seven beagle recipients surviving 2-11 years after allotransplantation of a left lung were available for study of pulmonary function. Significant reductions of ventilation and perfusion to the transplanted lung were documented by radionuclide scanning. These reductions in function were well-matched, however, and allowed relatively normal gas exchange, as measured by VD/VT, arterial PO2 and shunt fraction. The vasoconstrictor response of the transplanted lung to both hypoxia and stellate ganglion stimulation was comparable to that of the native lung. An abnormal rise in graft pulmonary vascular resistance and fall in PaO2 when the normal lung was made hypoxic suggest an inability of the transplanted lung to vasodilate and recruit blood vessels normally in response to increased blood flow. The animals were sacrificed at the conclusion of the pulmonary function testing. Pathologic study of the transplanted lungs showed minimal changes of rejection in spite of the fact that these recipient animals received no immunotherapy after the second posttransplant week.

Allotransplantation of lung without immunosuppression after transplantation. I. Staged transplantation of bone marrow and lung

Six of 12 animals are alive 8–22 months after transplantation. Five of these animals and one which died of streptococcal pneumonia after pulmonary function testing demonstrated adequate pulmonary function in the transplant. One living recipient has not been studied. Four animals died of a “wasting syndrome” thought to be related to radiation damage to the pancreas rather than graft-versus-host reaction. One animal was killed with a severe skin eruption of unknown cause.