RESUMEN
Allogeneic hematopoietic cell transplantation (HCT) can be curative for both myelodysplastic syndromes (MDS) and lymphoid malignancies. Little is known about the efficacy of allogeneic HCT in patients in whom both myeloid and lymphoid disorders are present at the time of HCT. We analyzed the outcomes in 21 patients with MDS and concurrent lymphoid malignancy when undergoing allogeneic HCT. A total of 17 patients had previously received extensive cytotoxic chemotherapy, including autologous HCT in 7, for non-Hodgkin lymphoma (NHL, n=7), Hodgkin lymphoma (HL, n=2), CLL (n=5), NHL plus HL (n=1), multiple myeloma (n=1) or T-cell ALL (n=1), and had presumably developed MDS as a consequence of therapy. Four previously untreated patients had CLL. A total of 19 patients were conditioned with high-dose (n=14) or reduced-intensity regimens (n=5), and were transplanted from HLA-matched or one Ag/allele mismatched related (n=10) or unrelated (n=9) donors; two patients received HLA-haploidentical related transplants, following a modified conditioning regimen. Currently, 2 of 4 previously untreated and 2 of 17 previously treated patients are surviving in remission of both MDS and lymphoid malignancies. However, the high non-relapse mortality among previously treated patients, even with reduced-intensity conditioning regimens, indicates that new transplant strategies need to be developed.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma , Mieloma Múltiple , Síndromes Mielodisplásicos , Acondicionamiento Pretrasplante , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Prueba de Histocompatibilidad , Humanos , Linfoma/mortalidad , Linfoma/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
Reduced intensity conditioning (RIC) prior to allogeneic hematopoietic cell transplantation (HCT) has shown promise in lowering the incidence of post-transplant complications including infection and graft-versus-host disease. T-cell-mediated graft rejection, however, remains a crucial factor in determining how 'mild' a level of immunosuppression can be administered. Understanding the kinetics of resistance responses as well as the role of CD4+ and CD8+ T cells underlies the development of protocols to circumvent resistance and support hematopoietic engraftment. In these studies, a major histocompatibility complex (MHC)-matched/minor histocompatibility antigen (MiHA) disparate RIC HCT model was developed in which resistance against donor hematopoietic progenitors as well as mature peripheral blood cells could be assessed. Interestingly, resistance was diminished in the absence of either host CD4+ or CD8+ T cells. However, its impairment was more severe in CD4-/- mice where resistance was not detected. Host CD4+ T cells were required for optimal expansion of specific (H60) T-cell receptor (TCR) expressing host anti-donor MiHA reactive CD8+ T cells following HCT. These observations demonstrate a critical role for host CD4+ T cells in resistance against MiHA disparate HCT. This RIC HCT resistance model will be useful for the analysis of the barrier to engraftment mediated by host T cells and the development of strategies to support engraftment.
Asunto(s)
Trasplante de Médula Ósea , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Supervivencia de Injerto/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Acondicionamiento Pretrasplante , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor/metabolismo , Donantes de Tejidos , Inmunología del Trasplante , Trasplante HomólogoRESUMEN
We have used affinity chromatography to identify proteins that interact with Nap1, a protein previously shown to play a role in mitosis. Our studies demonstrate that a highly conserved protein called Sda1 binds to Nap1 both in vitro and in vivo. Loss of Sda1 function causes cells to arrest uniformly as unbudded cells that do not increase significantly in size. Cells arrested by loss of Sda1 function have a 1N DNA content, fail to produce the G1 cyclin Cln2, and remain responsive to mating pheromone, indicating that they arrest in G1 before Start. Expression of CLN2 from a heterologous promoter in temperature-sensitive sda1 cells induces bud emergence and polarization of the actin cytoskeleton, but does not induce cell division, indicating that the sda1 cell cycle arrest phenotype is not due simply to a failure to produce the G1 cyclins. The Sda1 protein is absent from cells arrested in G0 and is expressed before Start when cells reenter the cell cycle, further suggesting that Sda1 functions before Start. Taken together, these findings reveal that Sda1 plays a critical role in G1 events. In addition, these findings suggest that Nap1 is likely to function during G1. Consistent with this, we have found that Nap1 is required for viability in cells lacking the redundant G1 cyclins Cln1 and Cln2. In contrast to a previous study, we have found no evidence that Sda1 is required for the assembly or function of the actin cytoskeleton. Further characterization of Sda1 is likely to provide important clues to the poorly understood mechanisms that control passage through G1.
Asunto(s)
Proteínas de Ciclo Celular/farmacología , Ciclo Celular/efectos de los fármacos , Proteínas Nucleares , Proteínas de Saccharomyces cerevisiae , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cromatografía de Afinidad , Ciclina G , Ciclinas/efectos de los fármacos , Ciclinas/metabolismo , Fase G1/efectos de los fármacos , Mutación , Proteína 1 de Ensamblaje de Nucleosomas , Unión Proteica , Proteínas/metabolismo , ARN Ribosómico/efectos de los fármacos , Temperatura , Técnicas del Sistema de Dos Híbridos , Levaduras/genética , Levaduras/fisiologíaRESUMEN
Azorhizobium caulinodans employs both cytochrome bd (cytbd; quinol oxidase) and cytcbb3 (cytc oxidase) as terminal oxidases in environments with very low O2 concentrations. To investigate physiological roles of these two terminal oxidases both in microaerobic culture and in symbiosis, knockout mutants were constructed. As evidenced by visible absorbance spectra taken from mutant bacteria carrying perfect gene replacements, both the cytbd- and cytcbb3- mutations were null alleles. In aerobic culture under 2% O2 atmosphere, Azorhizobium cytbd- and cytcbb3- single mutants both fixed N2 at 70 to 90% of wild-type rates; in root nodule symbiosis, both single mutants fixed N2 at 50% of wild-type rates. In contrast, Azorhizobium cytbd- cytcbb3-double mutants, which carry both null alleles, completely lacked symbiotic N2 fixation activity. Therefore, both Azorhizobium cytbd and cytcbb3 oxidases drive respiration in environments with nanomolar O2 concentrations during symbiotic N2 fixation. In culture under a 2% O2 atmosphere, Azorhizobium cytbd- cytcbb3- double mutants fixed N2 at 70% of wild-type rates, presumably reflecting cytaa3 and cytbo (and other) terminal oxidase activities. In microaerobic continuous cultures in rich medium, Azorhizobium cytbd- and cytcbb3- single mutants were compared for their ability to deplete a limiting-O2 sparge; cytbd oxidase activity maintained dissolved O2 at 3.6 microM steady state, whereas cytcbb3 oxidase activity depleted O2 to submicromolar levels. Growth rates reflected this difference; cytcbb3 oxidase activity disproportionately supported microaerobic growth. Paradoxically, in O2 limited continuous culture, Azorhizobium cytbd oxidase is inactive below 3.6 microM dissolved O2 whereas in Sesbania rostrata symbiotic nodules, in which physiological, dissolved O2 is maintained at 10 to 20 nM, both Azorhizobium cytbd and cytcbb3 seem to contribute equally as respiratory terminal oxidases.