We investigated the impact of the number of infused and reconstituted immunocompetent cells including dendritic cells (DCs) on clinical outcome of patients with hematologic malignancies undergoing an allogeneic peripheral blood stem cell transplantation. Sixty-nine consecutive patients with hematologic malignancies were included in the analysis. The median age of the cohort was 32 years (range: 2-62 years) and there were 39 (57%) males. Twenty-one (30%) patients relapsed with a cumulative incidence of 44 % +/- 14% at a median follow up of 28 months. On a multivariate analysis, a high plasmacytoid dendritic cell (PC) content in the graft was associated with higher risk of relapse. The patients were further categorized based on the median PC counts in the graft as high (> or =2.3 x 10(6)/kg) and low (<2.3 x 10(6)/kg) groups. The baseline characteristics of these 2 groups were comparable. The group that had a high PC content in the graft had significantly higher risk of relapse and lower overall survival (OS) and event-free survival (EFS). Our data suggests that PC content in the graft predicts clinical outcomes such as relapse and survival in patients with hematologic malignancies undergoing an allogeneic HLA matched related peripheral blood stem cell transplantation. There is potential for pretransplant manipulation of this cellular subset in the graft.
We have prospectively analyzed cellular immune reconstitution (IR) in 63 consecutive pediatric patients with beta thalassemia major who underwent an HLA matched related allogeneic bone marrow transplant (BMT). Samples from bone marrow graft and posttransplant peripheral blood samples from recipients at specified time points were assessed for IR of cellular subsets. The median age of the cohort was 7 years, and there were 37 (59%) males. A CD34 cell dose above the median value of 7.3 x 10(6)/kg had a lower incidence of bacterial (P = .003) and fungal (P = .003) infections in the posttransplant period, and was not associated with an increased risk of graft-versus-host disease (GVHD). Among cases that did develop grade II-IV GVHD the absolute CD8 (116 versus 52 cells/microL, P = .012), CD8 naïve (74 versus 9 cells/microL, P = .005), and CD8 memory counts (44 versus 21 cells/microL, P = .010) were significantly higher on day 15. Fifteen patients (24%) rejected their graft (7 primary and 8 secondary). The day 28 natural killer (NK) cell count was significantly associated with secondary graft rejection, event-free survival (EFS), and overall survival (OS) (P = .044, .013, and .034, respectively). On a multivariate analysis, patients with a day 28 NK cell count below the median value of 142/microL had a significantly higher rejection rate (hazard ratio [HR] = 11.1, P = .038) and a lower EFS (HR = 16.3, P = .034).
Dendritic cells (DC) are antigen-presenting cells involved in induction and regulation of immune responses. We investigated the impact of the number of infused and day 28 dendritic cells on the development of acute and chronic GVHD (aGVHD, cGVHD). Monocytoid (MC) and plasmacytoid (PC) dendritic cells were characterized as lin(-)HLA-DR(+)CD11c(+) and lin(-)HLA-DR(+)CD123(+), respectively. Sixty-eight consecutive patients who underwent HLA matched related granuloyte-colony stimulating factor (G-CSF) mobilized allogeneic PBSCT, from February 2005 to May 2006, were included in the analysis. Twenty-three patients developed aGVHD (grade II-IV) and 21 patients had cGVHD. On a univariate analysis the day 28 total DC and the day 28 MC and PC dendritic cells as continuous variables were significantly associated with development of aGVHD and cGVHD. Using an ROC plot analysis a cutoff value for total DC = 10.7/microL, MC = 9.7/microL, and PC = 4.5/microL on day 28 gave the highest likelihood ratios for aGVHD (2.7, 2.14, and 3.29, respectively). On a multivariate analysis, a low day 28 PC (
Wiskott Aldrich Syndrome (WAS) is an X-linked recessive disorder associated with severe thrombocytopenia, eczema, bloody diarrhea, profound immunodeficiency and an increased risk of malignancies. More than 200 mutations have been described in the gene encoding the WAS protein (WASP). We report here the molecular basis of WAS in six patients from India. Diagnosis of WAS/X- linked thrombocytopenia (XLT) was based on low platelet count (9000– 1, 25,000/mm3), presence of small platelets (mean: 6.2fl) and detection of WASP by flowcytometry. Patients evaluated in the study could be classified as classical WAS (n=3) and XLT (n=3) depending on the clinical severity of their disease (Zhu et.al 1995). All 12 exons and flanking splice-sites of WAS gene were amplified by polymerase chain reaction (PCR) using primers and PCR conditions adopted with modifications from Kwan et al (PNAS1995;92:4706). Mutation analysis was accomplished by conformation sensitive gel electrophoresis (CSGE) and direct sequencing. Abnormal banding pattern was observed only in 4 patients after CSGE analysis. c.995 C>T could not be detected by CSGE but was detected by direct sequencing. The types of molecular defects identified in five patients were as follows: nonsense - 2, deletion - 1 and duplication - 1. Three of these alterations (see table) have been reported previously and are associated with classical WAS. In patients detected to have nonsense mutations, flowcytometric analysis of WASP exhibited high values (table) not consistent with reported western blotting data in these mutations. c.307+10-11dupC was observed in two patients (brothers) with thrombocytopenia, small platelets and mild bleeding. This duplication is not a reported polymorphism. Though this duplication changes the acceptor splice site prediction score from 0.83 to 0.91, its functional significance has not been determined and requires further evaluation. The sixth patient in our study had thrombocytopenia (15,000–45,000/mm3), small platelets (4.8–7.2 fl), mild bleeding, similar family history and normal expression of WASP (86.2%). No mutation has been identified in the coding region of WAS gene in this patient either by CSGE or direct sequencing. Our data shows that the molecular basis for WAS is heterogenous in India. This is the first study evaluating mutations in WAS gene from India. Further mutation screening of patients with WAS will allow the genetic definition, phenotype-genotype corelation, carrier detection and prenatal diagnosis of this condition. Molecular defects observed in WAS patients Patient ID Flow cytometry (%) Mutation *-Reported mutation, ♦-Functional Significance not known PD-22 WASP D1-98.5, WASPB9 - 94.8 c.665C>T, p.Arg211X* PD-16 WASP B9- 6.7 c. 1035-1036 delG, p.Gly314ValfsX120* PD-21 WASP D1-97.2, WASP B9-91.2 c.995 C>T, p. Arg321X* PD-34, PD-35 (siblings) WASP D1-3.6, WASP B9-2; D1-1.8, B9-1 c.307+10-11 dupC♦ PD-28 WASP D1 - 86.2 Mutation not detected
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