The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells.

We have examined how the host environment influences the graft-vs-leukemia (GVL) response following transfer of donor T cells to allogeneic chimeras. Donor T cells induce significant GVL when administered in large numbers to established mixed chimeras (MC). However, when using limiting numbers of T cells, we found that late transfer to MC induced less GVL than did early transfer to freshly irradiated allogeneic recipients. Late donor T cell transfer to MC was associated with marked accumulation of anti-host CD8 cells within the spleen, but delayed kinetics of differentiation, reduced expression of effector molecules including IFN-gamma, impaired cytotoxicity, and higher rates of sustained apoptosis. Furthermore, in contrast to the spleen, we observed a significant delay in donor CD8 cell recruitment to the bone marrow, a key location for hematopoietic tumors. Increasing the numbers of T cells transferred to MC led to the enhancement of CTL activity and detectable increases in absolute numbers of IFN-gamma(+) cells without inducing graft-vs-host disease (GVHD). TLR-induced systemic inflammation accelerated differentiation of functional CTL in MC but was associated with severe GVHD. In the absence of inflammation, both recipient T and non-T cell populations impeded the full development of GVHD-inducing effector function. We conclude that per-cell deficits in the function of donor CD8 cells activated in MC may be overcome by transferring larger numbers of T cells without inducing GVHD.

Radiation protocols determine acute graft-versus-host disease incidence after allogeneic bone marrow transplantation in murine models.

PURPOSE: Effects of radiation sources used for total body irradiation (TBI) on Graft-versus-Host Disease (GvHD) induction were examined. MATERIALS AND METHODS: In a T cell receptor (TCR) transgenic mouse model, single fraction TBI was performed with different radiation devices ((60)Cobalt; (137)Cesium; 6 MV linear accelerator), dose rates (0.85; 1.5; 2.9; 5 Gy/min) and total doses before allogeneic bone marrow transplantation (BMT). Recipients were observed for 120 days. Different tissues were examined histologically. RESULTS: Acute GvHD was induced by a dose rate of 0.85 Gy/min ((60)Cobalt) and a total dose of 9 Gy and injection of 5 x 10(5) lymph node cells plus 5 x 10(6) bone marrow cells. Similar results were obtained using 6 MV linear accelerator- (linac-) photons with a dose rate of 1.5 Gy/min and 0.85 Gy/min, a total dose of 9.5 Gy and injection of same cell numbers. TBI with (137)Cesium (dose rate: 2.5 Gy/min) did not lead reproducibly to lethal acute GvHD. CONCLUSIONS: Experimental TBI in murine models may induce different immunological responses, depending on total energy, total single dose and dose rate. GvHD might also be induced by TBI with low dose rates.

Cortisol as a possible marker of metastatic adrenocortical carcinoma: a case report with 3-year follow-up.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumour, sometimes causing glucocorticoid hypersecretion. Treatment guidelines have not been established, but are currently under investigation. CASE REPORT: A 55-year-old Caucasian woman presented with adrenal Cushing's disease. Histological examination after a left adrenalectomy revealed a benign tumour. Postoperatively, elevated serum cortisol levels normalized. Hypercortisolism occurred again two years later. Diagnostic work-up revealed hepatic metastatic lesions of an ACC which were treated by right hemihepatectomy. Initial histological diagnosis was revised according to the increased proliferative changes. Postoperatively, cortisol declined to normal levels. Treatment with mitotane (o, p'-DDD) as a cytostatic agent was not tolerated. One year later, the patient was diagnosed with a solitary osseous metastasis at the left side of the sacrum because of back pain. Following curettage and stabilization, radiotherapy of this region with 37.5 Gy was performed, improving slightly elevated cortisol levels and neurological symptoms. CONCLUSION: Careful clinical and radiographic follow-up of patients with ACC are important. In this case of oligometastasizing ACC, serum cortisol values correlated with the clinical course. An aggressive multimodal treatment, including repeated surgical approach with consolidating radiotherapy in cases of incomplete resection, might be indicated to provide symptom control and possible long-term survival in oligometastatic disease of ACC.

Radiation recall pneumonitis induced by gemcitabine.

BACKGROUND: Radiation recall pneumonitis describes a very rare reaction in a previously irradiated area of pulmonary tissue after application of pharmacological agents. A case of recall pneumonitis induced by gemcitabine is reported. CASE REPORT: A 64-year-old female patient with metastasized esophageal carcinoma received simultaneous chemoradiotherapy of the upper mediastinum with 50.4 Gy and cisplatin/5-fluorouracil. 8 months later she was scheduled for salvage chemotherapy with gemcitabine (1,000 mg/m(2) days 1 and 8) and docetaxel (75 mg/m(2) day 8) due to locally progressive disease. After having received gemcitabine on day 1 of the second course, the patient developed dry cough, subfebrile temperatures and dyspnea within 48 h. A CT of the thorax revealed newly developed bilateral pulmonary ground-glass opacity corresponding to the previous radiation fields. Chemotherapy was stopped and systemic application of prednisolone was initiated. 2 months later symptoms had resolved with a control CT of the thorax showing complete regression of the pulmonary changes. CONCLUSION: Gemcitabine-induced recall pneumonitis is a rarely reported phenomenon and should be taken into account even after extended time interval to the previous radiotherapy.

Influence of radiation protocols on graft-vs-host disease incidence after bone-marrow transplantation in experimental models.

Bone-marrow transplantation is an approved curative treatment for many hemato- and oncologic diseases. Nevertheless, the severe acute clinical course of graft-vs-host disease (GVHD) after allogeneic bone-marrow transplantation is frequently fatal, and is to date not curable. Acute GVHD must, therefore, be prevented from the start of the bone-marrow transplantation by immunosuppressive medication, causing sometimes serious side effects. Therefore, new preventive strategies are tested, starting with animal experiments. Often mice are chosen for this kind of trial, and the clinical protocol of bone-marrow transplantation is transferred into the experimental settings. The first step to induce an acute GVHD is whole-body irradiation of the recipients. Several methods are available for this purpose: the most common is a 60cobalt source (gamma-irradiation); less common are a 137cesium source (gamma-irradiation) and a linear (particle) accelerator (photons). Differences between these radiation techniques can occur and can unexpectedly interfere with the results of the experiments. In this chapter, the materials and methods for bone-marrow transplantation in mice, with particular emphasis on the different radiation techniques, are explained; furthermore, the advantages and disadvantages in regard to the underlying physical principles will be discussed.