The functional relevance of passenger leukocytes and microchimerism for heart allograft acceptance in the rat.

With an organ transplant, hematopoietic donor cells are transferred to the recipient. To study the relevance of the resulting microchimerism for allograft acceptance, we analyzed a rat model of cyclosporine-induced tolerance for strongly incompatible heart allografts. Using a monoclonal antibody that detects a donor-specific CD45 allotype (RT7a), we selectively depleted donor leukocytes at different times after transplantation (days 0 or 18). Depletion was similarly effective at both times. However, only depletion on day 0 prevented tolerance induction and was associated with severe acute or chronic graft rejection. This indicates that passenger leukocytes have an essential immunomodulatory effect on the induction phase of allograft acceptance.

[10 years transplantation of bone marrow and hematopoietic stem cells in adults at the Hannover Medical School]. / Zehn Jahre Transplantation von Knochenmark und hämatopoetischen Stammzellen bei Erwachsenen an der Medizinischen Hochschule Hannover.

PATIENTS AND METHODS: From January 1986 until August 1995 230 adult patients received an allogeneic or autologous transplantation of bone marrow or hematopoietic blood stem cells. The conditioning and myeloablative treatment regimens were chosen according to the underlying disease and type of transplant. RESULTS: The observation period comprises 1 to 115 months after transplantation. After allogeneic transplantation from HLA-identical family donors, the probabilities of disease-free survival were for acute myeloid leukemia in first complete remission (CR) (n = 35) 77%, for acute lymphoid leukemia in 1st CR (n = 7) 72% and in 2nd CR (n = 10) 40%, in first chronic phase of chronic myeloid leukemia (n = 34) 50% and in severe aplastic anemia (n = 7) 100%. Following myeloablative therapy and autologous transplantation the probabilities of disease-free survival were 47% in relapsed Hodgkin's disease (n = 22) and 42% for relapsed high-grade non-Hodgkin's lymphoma (n = 12). Eight of 10 patients with acute myeloid and 7 of 8 with acute lymphoid leukemia suffered a leukemic relapse after autologous bone marrow transplantation. Three of 8 patients with relapsed testicular cancer survived relapse-free. Treatment failures were due to more advanced acute graft versus host disease after allogeneic transplantation and caused by relapse after autologous transplantation. Current protocols evaluate the allogeneic transplantation of enriched CD34+ blood stem cells. In chronic myeloid leukemia the autologous transplantation of blood stem cells after myeloablative therapy is being studied.

[Radiation dose in critical organs due to non-coplanar irradiation of the hypophysis]. / Strahlenbelastung von Risikoorganen durch nonkoplanare Bestrahlung der Hypophyse.

BACKGROUND: In order to estimate the somatic and genetic risk associated with a non-coplanar linac-based radiation technique of the pituitary gland, systematic secondary-dose measurements in a phantom and sample measurements of the dose near critical organs of patients were performed. PATIENTS AND METHODS: For measurements of the dose outside the primary radiation field an acrylic-PVC phantom was used which was irradiated with a single field (4 x 4 cm2). Eight patients with pituitary tumors were treated isocentrically with a combination of sagittal and transverse rotational arcs. To measure the dose in critical organs. LiF thermoluminescence dosimeters (TLD) in chip form were placed onto 1 eyelid, the skin over the thyroid, and the patient's clothes covering the region of breasts and ovaries of female patients and the testicles of male patients. Measurements were performed for all patients during 1 sagittal irradiation and for the majority of patients during 1 transverse irradiation. RESULTS: The phantom measurements demonstrated that the secondary dose measured on the patients surface can be considered as a good approximation for the dose in adjacent organs. The median dose in critical organs for sagittal irradiation was in the range of 25.8 mGy (eyes) to 1.9 mGy (testicles), and for transverse irradiation in the range of 23.3 mGy (eyes) to 1.3 mGy (testicles). The ratio of median organ doses for sagittal and transverse irradiation was 2.1 for the thyroid gland, 1.1 for the eyes, and 1.5 for the other organs. CONCLUSIONS: The dose in critical organs due to non-coplanar irradiation of the pituitary gland is only a small fraction of the dose delivered to the reference point of the planning target volume. The risk of a radiation-induced tumor and a genetic consequence associated with these small doses is generally less than 1% and 0.1%, respectively.

In vivo effects of interleukin-6 on thrombopoiesis in healthy and irradiated primates.

We have studied the in vivo effects of recombinant human interleukin-6 (rhIL-6) on hematopoiesis in eight healthy and nine irradiated cynomolgus monkeys. Of the healthy animals, three received rhIL-6 alone (10 micrograms/kg/d, subcutaneously [SC]), one received rhIL-6 in combination with rhIL-3 (10 micrograms/kg/d, SC), one received rhIL-6 in combination with recombinant cynomolgus granulocyte-macrophage colony-stimulating factor (rcGM-CSF; 10 micrograms/kg/d, SC), two received rhIL-6 in combination with recombinant human granulocyte-CSF (rhG-CSF; 10 micrograms/kg/d, SC), and one received rhIL-6 in combination with recombinant human leukemia inhibitory factor (rhLIF; 10 micrograms/kg/d, SC). All animals were treated for at least 2 weeks with rhIL-6 or the above mentioned combinations. rhIL-6 alone significantly increased the peripheral blood platelet counts (2- to 3.5-fold). The platelets reached a plateau between days 10 and 15 of treatment. No synergistic effects on platelet numbers were observed when rhIL-6 was combined with rhIL-3, rcGM-CSF, rhG-CSF, or rhLIF. In addition to rhIL-6, only rhLIF increased the platelet numbers when administered alone. To test whether rhIL-6 might also protect the animal from thrombocytopenia or shorten the time of thrombocytopenia after irradiation, we treated nine animals with total body irradiation (3.8 Gy). Six of the animals were additional treated with rhIL-6 (4 with 10 micrograms/kg/d; and 2 with 100 micrograms/kg/d) from day -1 or +1 to day 28 post irradiation. In these animals, rhIL-6 at the same dose effective in healthy animals (10 micrograms/kg/d) was not capable of protecting the animals from platelet nadir. However, when pegylated rhIL-6 was used at a dosage of 100 micrograms/kg/d post irradiation, the mean of the nadirs was 71,000/microL as compared with 39,000/microL in control animals and the time of thrombocytopenia was shorter (3 v 5 days). In all animals (healthy and irradiated), rhIL-6 did not increase the number of bone marrow megakaryocytes but induced a right shift of DNA ploidy in megakaryocytes. These data suggest that IL-6 acts as "thrombopoietin"-like activity, but not as "megakaryocyte-CSF"-like activity.

The influence of ionizing radiation on the CLARION 1.2 cochlear implant during radiation therapy.

OBJECTIVE: This study aimed to determine the maximum dose of radiation the CLARION 1.2 cochlear implant can withstand safely. INTRODUCTION: Cochlear implants restore functional hearing to patients with sensorineural deafness. Because some patients may need radiation therapy, it is important to investigate the influence of ionizing radiation on cochlear implant function. METHODS: This study tested the function of four CLARION 1.2 implants (Advanced Bionics, Sylmar, CA, U.S.A.) after varying radiation treatments with gamma rays. The first implant received a cumulative dosage of 69 Gy over nine treatments (single doses between 0.1-30 Gy). The second was irradiated with a total of 90 Gy, receiving three treatments of 30 Gy each. The third and fourth received doses more typical of patient therapy (i.e., 2 Gy) approximately 30 times, for a cumulative dosage of approximately 60 Gy. Implant function was tested after every treatment; the CLARION implant incorporates a back-telemetry system, allowing impedance and current output testing. RESULTS: Despite the type of treatment, the results were quite consistent: difficulties in function occurred when the cumulative dosage inside the implant was approximately 60 Gy. The first implant recovered completely and the second recovered partially. DISCUSSION: The CLARION 1.2 cochlear implant seems to safely withstand approximately 60 Gy of radiation before experiencing functional difficulties. In a clinical situation, the implant would not likely be in the target volume irradiated, and thus the patient's therapeutic cumulative dosage might be higher.