Edward C. Saltzstein

Graft versus Host Inhibition: Fetal Liver and Thymus Cells to Minimize Secondary Disease

Long-lived radiation chimeras were produced in mice diflering at the major histocompatibility locus. Survival occurred in lethally irradiated recipients inoculated with allogeneic fetal liver and allogeneic fetal thymus cells in combination. The survival rate was equal or superior to that of mice with transplanted syngeneic fetal, neonatal, or adult hematopoietic cells.

Adoptive Immunotherapy of Spontaneous Leukemia-Lymphoma in AKR Mice

Barnes, et al, (3) first proposed that the transplantation of allogeneic bone marrow might serve as an aggressive antileukemic treatment. They reasoned that following lethal irradiation, residual leukemia cells might be eliminated through a “reaction of immunity” carried out by the transplanted cells. Mathe proposed the term adoptive immunotherapy to describe this effect (10). New insights in immunobiology have caused a resurgence of interest in immunotherapy as an adjunct to currently available therapy of cancer. Many reasons exist which make it difficult to manipulate a patient’s own immune system so that it can become decisively effective against his own tumor. Transplantation of immunocompetent cells from a normal individual to the tumor-bearing patient offers an alternative immunotherapeutic approach. Unfortunately, transplanted immunocompetent cells also recognize and react against histocompatibility antigens present on the normal tissues of the host, causing potentially lethal graft-versus-host (GVH) disease, the major complication of adoptive immunotherapy.

Prolonged survival of AKR mice following allogeneic bone marrow transplantation.

Die Mehrzahl der AKR Mäuse, die nach Immunosuppression und Transplantation von Knochenmark und lymphoiden Zellen allogener H2-identischer Spender die «Graft-versus-Host» Reaktion überlebten, zeigten signifikant verlängerte mittlere Überlebenszeiten gegenüber Kontrolltieren, welche mit Immunosuppression allein oder Immunosuppression plus sygenen Zellen behandelt wurden.

Combined fetal liver and thymus for hematopoietic reconstitution of allogeneic radiation chimeras.

Summary Femoral bone marrow cellulari–ty, CFU concentration, and CFU content were markedly subnormal in allogeneic radiation chimeras that had been produced with bone marrow cells from adult donors. 2. Marrow cellularity was restored to normal within 3 weeks when liver or liver plus thymus from fetal donors was the tissue transplanted. 3. In chimeras produced with fetal cell transplants, marrow CFU increased at a slower rate than did differentiated marrow cells. However, at 77 ± 7 days, chimeras produced with fetal liver plus fetal thymus cells had normal numbers of femoral CFU and this level was significantly higher than in chimeras produced with fetal liver without thymus cells. 4. Hematopoietic repopulation of allogeneic radiation chimeras using combined fetal liver and thymus cell transplants was equal or superior to that achieved with fetal liver alone or adult bone marrow despite the fact that with the latter tissues 2 to 5 times as many hematopoietic stem cells had been transplanted. Expert technical assistance was provided by Miss Brigid M. Finnegan, Mrs. Alice C. Grady, and Mrs. Evangeline R. Reynolds.

Perfusion of an isolated renal allograft.

Abstract A successful technic of isolated perfusion of the canine renal allograft is described. The rationale of the potential applications of the technic, both of delivering high concentrations of immunosuppressive drugs directly to a rejecting kidney and thus obviating systemic side effects, and of the ease of pure renal vein blood sampling, is discussed.

Growth of human tumors in lethally irradiated mice reconstituted with syngeneic fetal liver cells.

Transplantation into lethally irradiated mice of hematopoietic and lymphoid cells from immature donors which hypothetically will not mount a cell mediated attack against simultaneously inoculated human tumor cells has resulted in tumor engraftment and growth in long‐term surviving radiation chimeras. Twenty‐four hours after lethal irradiation, A or CBA mice were given iv injections of 2 × 107 fetal liver cells from syngeneic donors of 14, 16, or 18 days of embryonation and sc injections of 1, 3, or 6 × 106 human choriocarcinoma (C‐1, C‐2, and C‐3) cells or human breast carcinoma (B‐1) cells that had been maintained in culture. Palpable tumors ≧ 5 mm were noted in 18/22 mice injected with C‐1, 9/16 with C‐2, 10/10 with C‐3, and 18/30 with B‐1. Tumors of 17 (31%) of mice remained palpable until death of the animal or until termination of the experiment 100 days post inoculation. Histologic study of autopsy specimens revealed malignant tumors with occasional pulmonary metastases. Human chorionic gonadotropin was found in the serum of mice that received choriocarcinoma cells.

Brief Communication: Low-Dose Chemotherapy as a Prelude to Intensive Treatment of Spontaneous Leukemia-Lymphoma in AKR Mice

Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.