Allogenic transplant of canine peripheral blood stem cells mobilized by recombinant canine hematopoietic growth factors

We have studied graft-versus-host disease (GVHD) after transplantation of allogeneic peripheral blood stem cells (PBSC) mobilized by either recombinant canine granulocyte colony-stimulating factor (rcG-CSF) alone or combined with stem cell factor (rcSCF). These studies were prompted by the observation of extremely rapid and sustained engraftment of growth factor-mobilized PBSC in the autologous setting using genetically marked cells and changes in function of T lymphocytes from donors that had undergone mobilization. Specifically, lymphocytes from growth factor-treated donors were hyporesponsive in mixed leukocyte culture and in response to Con A, raising hopes that GVHD in dogs given growth factor mobilized allogenic PBSC might be altered in a beneficial way. Eighteen dogs were given a median of 17.1 x 10(8) PBSC/kg from littermate donors after 920 cGy of total body irradiation without postgrafting immunosuppression. Donors were either genotypically DLA-identical (n = 9) or DLA-haploidentical (n = 9). The median number of colony-forming unit-granulocyte macrophage (CFU-GM) infused was 27 x 10(4)/kg, and the number of CD34+ cells in the transplant was on the order of 4.6 x 10(6)/kg. The dogs received a median of 52.8 x 10(7) CD4 cells/kg and 13.7 X 10(7) CD8 cells/kg. All 18 dogs had prompt hematopoietic engraftment of donor cells as assessed by chimerism studies using variable number tandem repeat, as well as cytogenetic markers. Three of the nine dogs given grafts from DLA- identical littermates had fatal GVHD, five had transient GVHD, and one had no GVHD. All nine DLA-haploidentical recipients of PBSC developed fatal hyperacute GVHD. In conclusion, the expectation about rapid engraftment was fulfilled. However, incidence and severity of acute GVHD after transplantation of mobilized PBSC were not different than previously reported for nonmobilized PBSC or marrow. This model will allow for further studies, including T-cell depletion to minimize GVHD without increasing graft rejection.     

Functional dendritic cells are required for transfusion-induced sensitization in canine marrow graft recipients

Untransfused dogs given 9.2 Gy total-body irradiation and hematopoietic grafts from DLA-identical littermate donors uniformly achieve sustained engraftment, whereas dogs given three transfusions (Tx) of whole blood from the intended marrow donor 24, 17 and 10 days pretransplant uniformly reject their graft. Sensitization appears to be mediated by peripheral blood mononuclear cells and can be prevented by prior irradiation of the Tx product with UV light, known to inactivate leukocytes, in particular, cells with accessory function. In the present study we investigated which leukocyte population was responsible for Tx-induced sensitization and subsequent marrow graft rejection. Surprisingly, neither monocytes nor macrophages or dendritic cells induced sensitization, and all dogs so treated achieved engraftment; however, all four evaluable dogs transfused with UV- exposed blood to which small numbers of normal dendritic cells (12.5 x 10(3)/kg) were added rejected their marrow graft. Among five dogs given UV-exposed blood and normal monocytes (12.5 x 10(3)/kg) only one rejected its graft, and four achieved sustained engraftment. We conclude that donor dendritic cells are necessary, albeit not sufficient for in vivo sensitization. Sensitization is prevented by elimination or inactivation of dendritic cell.     

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft- versus-host disease

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.     

Estimates of prospective change in self-rated health in older people were biased owing to potential recalibration response shift

ObjectiveEvidence shows that self-rated health (SRH) remains remarkably stable during aging. Individuals may change their conceptualization of health or revise their standard of good health when facing health decline. Although this “response shift” phenomenon is potentially beneficial to the individual, it also challenges comparison of SRH assessments over time. The present study investigates this response shift.Study Design and SettingData come from two waves (T1 and T2) of the Longitudinal Aging Study Amsterdam (N: 1,274; age: 55–89 years; mean follow-up: 3.6 years). Linear regression models were used for predicting SRH at T1 and T2. To capture changes in individual health standards, we administered a then-test at T2, asking respondents to retrospectively rate their health at T1 again.ResultsNo support was found for a changed conceptualization of SRH after health decline: predictive models for SRH at T1 and T2 were not significantly different. In the subgroup that reported identical SRH at T1 and T2, participants who experienced incident diseases were three times more likely to retrospectively overrate health at T1 with the then-test, suggesting that they had a lowered health standard.ConclusionOlder people's concept of health remains stable when they encounter significant health problems, but they potentially lower their standard of good health over time.     

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.