Abstract 1013
Dendritic cells (DCs) play a pivotal role in initiating and modulating immune responses to pathogens. Data from experimental allogeneic bone marrow transplantation showed impaired DC ...function post-transplant as DCs produced mostly TNF-alfa with low amounts of IL-10, IL-12 and IFN-alpha, did not express co-stimulatory molecules upon activation with fungal antigens and were unable to phagocytose fungi. In vitro and in vivo data demonstrated Thymosin alpha 1 (T alpha 1), a naturally occurring peptide, induced DC activation, maturation and differentiation. T alpha 1 stimulated phagocytosis and functional maturation of murine pulmonary DCs upon exposure to Aspergillus conidia, accelerated lymphoid cell recovery and activated protective Th1-dependent resistance to infection. In a murine model of allogeneic bone marrow transplantation with lethal pneumonia caused by an A. fumigatus challenge, T alpha 1 promoted balanced Th1/Treg immunity and protected mice from invasive aspergillosis 1, 2. The activation of innate immune system by T alpha 1 was mediated by distinct Toll-Like Receptor (TLR) signalling culminating in the activation of the p38 MAPK/NF-kB pathway. More recently, transcription profile of DCs exposed to T alpha 1 revealed a number of genes modulated by T alpha 1, including those involved in the regulation of the canonical/noncanonical NF-kB pathway in response to cellular stress and homeostasis. Accordingly, we designed a phase I/II clinical trial to determine the safety and efficacy of T alpha 1 administration in 30 recipients (12/30 with active disease at transplant) of HLA-matched sibling T cell-depleted stem cell transplants. Patients aged 20–69 years (median 46) with AML/MDS (12), ALL (6), lymphoma (7), MM (4), CLL (1) were conditioned with TBI or Melphalan, Thiothepa, and Fludarabine and given T alpha 1 (1.6 mg/day subcutaneously) from the day of transplant onwards for 16 weeks. Forty-five patients (25/45 with active disease at transplant), who were transplanted under the same protocol, served as controls. They were aged 20–67 years (median 53) with AML/MDS (20), ALL (4), lymphoma (11), MM (6), CLL (3), myelofibrosis (1). During and after T alfa 1 administration no adverse effects whatsoever were observed. Immune reconstitution was assessed by limiting dilution analyses of frequencies of CD4+ T cells that were specific for Aspergillus, Candida, CMV, Adenovirus, Herpes Simplex Virus, Varicella- Zoster Virus, Toxoplasma antigens. Normal donor values ranged from 600 to 1200/10e6 plated cells. Control transplant recipients acquired such pathogen-specific T cell responses from month 3 onwards in frequencies that ranged from 50 to 250/10e6 plated cells. In patients who received T alfa 1, pathogen-specific T cells appeared as early as 1 month after transplant in significantly higher frequencies which soon ranged from 250 to 500/10e6 plated cells. The cumulative incidence of non-relapse mortality (NRM) (mainly infection-related) was 33% in controls vs 7% in Thymosin-treated patients (p = 0.02). Thymosin administration did not impact upon the relapse rate (which was around 50% in both series). As a consequence of the improved TRM, Event-Free Survival was better in Thymosin treated patients (42% vs 20% in controls; p = 0.02). Multivariate analyses including diagnoses, disease status at transplant, conditioning regimen and donor lymphocyte infusions (during and after Thymosin administration) showed Thymosin treatment was a significant independent factor predicting a lower incidence of NRM (p=0.04) which tended to provide better survival (p = 0.09). In conclusion, this study shows that T alfa 1, a naturally occurring peptide of thymic origin which optimizes antigen presentation and T cell responses, could safely be administered after matched sibling T cell depleted hematopoietic transplants. T alfa 1appeared to protect from largely infectious NRM and to improve the survival of transplant recipients. It is worth noting that T cell depletion of the graft and the consequent lack of post-transplant pharmacological immune suppression may have facilitated the peptide’s immune regulatory action.
Off Label Use: Thymosin alfa 1 is a naturally occurring peptide of thymic origin that is reported to optimize antigen presentation and T cell responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy regimens is currently considered the standard of care for newly diagnosed acute promyelocytic leukemia (APL) ...patients. This combination has greatly contributed to convert APL from a frequently fatal disease to a highly curable one. However, there is lack of data on the impact of such therapies on patients' health-related quality of life (HRQOL).
The main objective of this study was thus to investigate long-term HRQOL of APL patients previously treated with ATRA plus anthracycline-based chemotherapy. The physical and mental HRQOL profile of these patients was compared with that of matched control subjects from the general population to identify specific areas most in need of attention in long-term follow-up care. A secondary objective was to outline symptoms' burden from the patients' perspective.
Data were gathered through an ongoing multicenter survivorship study that recruits APL patients previously enrolled in two large GIMEMA trials (i.e., AIDA0493 and AIDA 2000). In both trials, APL patients were treated with ATRA plus Idrarubicin (AIDA). The main inclusion criterion was having survived the initial diagnosis for more than 5 years and being in complete remission (CR). Generic HRQOL was assessed with the SF-36 that consists of 36 items covering eight generic health status/QoL domains: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE) and mental health (MH). All scales ranged between 0 and 100, with the higher scores representing better outcomes. Clinical significance was evaluated and eight points were considered to be a minimally important difference for the eight SF-36 scales. Mean SF-36 scores were compared to available national general population reference values (i.e., 1997 subjects without cancer) and all analyses were adjusted for age and gender. Symptom burden was assessed according to the M.D. Anderson Symptom Inventory (MDASI). Symptom severity was assessed for the following symptoms: fatigue, pain, sleep disturbance, drowsiness, poor appetite, shortness of breath, nausea, vomiting, dry mouth, numbness, difficulty remembering, distress and sadness. All items were rated on a numeric rating scale from 0 to 10, with the higher scores indicating a higher level of symptoms. These were categorized as “mild” (ratings between 0 and 3) and “moderate to severe” (ratings between 4 to 10).
Analysis is based on 136 adult APL patients who agreed to participate. At study participation, the mean age of patients was 52 years (55% males and 45% females) and the median time from diagnosis was 13 years (range: 4.5-20). Age and gender adjusted comparisons between APL patients and the general population norms revealed worse outcomes for the following scales: RP (P<.001) and RE (P<.001). Such differences were more than six times the magnitude of a clinically meaningful difference (i.e., at least 8 points), respectively for the physical (Δ=51 points) and the emotional scales (Δ=49 points) of the SF-36. Analysis within our patient cohort revealed that older APL patients (i.e., those aged more than 52 years) had a statically significant lower physical functioning (P<.001) and higher pain severity (P=.0448) than younger ones. Investigation of the HRQOL profile of patients by trial participation (i.e., AIDA 0493 vs. AIDA 2000) or time since diagnosis (cut-off median time of 13 years) revealed no difference in all scales of the SF-36. Fatigue was the most burdensome symptom being reported as moderate to severe in 35% of patients. Other frequently reported moderate to severe symptoms were: difficulty in remembering (30%), sadness and distress (29%).
Although ATRA plus anthracycline-based chemotherapy regimens have greatly increased cure rates in APL, the HRQOL of these patients is heavily affected by the consequences of the disease and treatment, that persists many years after diagnosis and treatment.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients undergoing full haplotype-mismatched hematopoietic transplantations may experience severe intractable invasive fungal infections. To verify whether an imbalanced production of T-helper 1 ...(TH1) and TH2 cytokines may be responsible for susceptibility to fungal infections, C3H/HeJ (H-2k) recipient mice were lethally irradiated, received transplantations with T-cell–depleted allogeneic bone marrow (BM) cells from mice ofH-2d haplotype, and were infected withCandida albicans. At different time-points after transplantation, mice were assessed for pattern of TH cytokine production and susceptibility to infection. The results show that a long-term, donor-type chimerism was achieved as early as 2 weeks after BM transplantation (BMT), at the time when high-level production of TH2 cytokines (interleukin-4 IL-4 and IL-10) and impaired production of TH1 cytokines (interferon-γ IFN-γ and IL-12 were observed. At this time, mice were highly susceptible to both disseminated and mucosal infections, as indicated by decreased survival, uncontrolled fungal growth, and failure to develop protective TH1 immunity. However, a predominant production of TH1 cytokines was observed by week 5 after BMT, at the time when mice developed donor-type protective TH1 responses and were resistant to infections. Therapeutic ablation of IL-4 or IL-10 greatly increased resistance to candidiasis. These results indicate that a dysregulated production of TH cytokines occurs in mice undergoing T-cell–depleted allogeneic BMT. The transient predominant production of TH2 cytokines over that of IL-12 impaired the ability of mice to develop antifungal TH1 resistance, an activity that could be efficiently restored upon treatment with TH2 cytokine antagonists.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Kallikrein-related peptidases are secreted serine proteases that exert stimulatory or inhibitory effects on tumor progression. A recent study demonstrated that kallikrein-related peptidase 5 (KLK5) ...concentration is elevated in serum of patients with ovarian carcinoma. At the moment, the presence of KLK5 in other ovarian pathological lesions is not clearly determined. Moreover, the possibility of a spontaneous humoral immune response to KLK5 has not been studied yet.
In this study, we examined KLK5 levels and antibody (IgG and IgM) response to KLK5 in the serum of 50 healthy women, 50 patients with benign pelvic masses, 17 patients with ovarian borderline tumors, and 50 patients with ovarian carcinomas, using 3 enzyme-linked immunosorbent assay tests available in-house.
At 95% specificity on healthy controls, 52% of patients with ovarian carcinoma showed high serum KLK5 (sKLK5) levels, whereas patients with benign pathological lesions or borderline tumors showed almost undetectable sKLK5 levels. Moreover, sKLK5 levels were positively associated to International Federation of Gynaecologists and Obstetricians stage suggesting a possible role of sKLK5 in ovarian cancer progression. Our results about humoral response showed elevated levels of KLK5-specific antibodies in 20% of patients with benign masses, 26% of patients with borderline tumors, and 36% of patients with ovarian carcinomas when compared with healthy controls. Interestingly, KLK5 antibodies were also found in patients with undetectable sKLK5 levels.
In conclusion, our results showed that KLK5 is a potential new biomarker to be used in combination with other biomarkers for ovarian cancer detection. Moreover, the existence of KLK5 antibodies suggests that KLK5 might represent a possible target for immune-based therapies.
Ideational apraxia is characterized by impaired knowledge of action concepts and proper object usage. The present functional magnetic resonance imaging study aimed at investigating the neural system ...underlying conceptual knowledge for proper object use in healthy subjects, when the effects of visuospatial properties and perceptual modality were taken into account. Subjects performed semantic decision tasks requiring retrieval of knowledge about either object functional purposes (functional task) or visuospatial object properties (visuospatial task) and perceptual control tasks. The semantic tasks were performed with pairs of either written object names or object drawings. Activation for the functional task in common for words and pictures, compared with the visuospatial and control tasks, was found in left parietal–temporal–occipital (PTO) junction, inferior frontal, anterior dorsal premotor, and presupplementary motor areas. Ventral inferior frontal cortex activation correlated negatively with reaction time in the functional condition. No specific activation characterized the visuospatial task compared with the functional task. The conceptual tasks, compared with the control tasks, demonstrated overlapping activation in left PTO junction, prefrontal, dorsal premotor, cuneus, and inferior temporal areas. These results outline the neural processes underlying conceptual knowledge for proper object use. The left ventral inferior frontal gyrus might facilitate behavioral decisions regarding functional/pragmatical object properties.
We designed a phase I/II clinical study to determine safety and efficacy of thymosin alpha1 (Talpha1) administration in recipients of one HLA haplotype (haploidentical) stem cell transplants for ...hematologic malignancies. Talpha1 administration did not cause acute or chronic graft versus host disease and was associated with significant improvement in polymorphonuclear (phagocytosis) and dendritic cell (phagocytosis, expression of costimulatory molecules, and cytokine production) functions. It was also associated with increased T-cell counts and earlier appearance of functional pathogen-specific T cell responses (by a sensitive limiting dilution assay that detects frequency of T cells specific for Aspergillus, Candida, CMV, ADV, VZV, HSV, Toxoplasma). Five of six haploidentical transplant recipients who received Talpha1 are alive and disease free at a median follow-up of 10 months after transplantation (range: 5-20). They experienced only a single nonlethal infectious episode and one patient developed fatal immune hemolytic anemia. At this very early stage of the clinical trial, we conclude Talpha1 administration is safe and may impact favorably on immune function. Larger numbers of patients and longer follow-up are, of course, needed to assess its impact on survival. PUBLICATION ABSTRACT
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
We designed a phase I-II clinical study to determine safety and efficacy of thymosin a1 (Ta1) administration in recipients of one HLA haplotype (haploidentical) stem cell transplants for hematologic ...malignancies. Ta1 administration did not cause acute or chronic graft versus host disease and was associated with significant improvement in polymorphonuclear (phagocytosis) and dendritic cell (phagocytosis, expression of costimulatory molecules, and cytokine production) functions. It was also associated with increased T-cell counts and earlier appearance of functional pathogen-specific T cell responses (by a sensitive limiting dilution assay that detects frequency of T cells specific for Aspergillus, Candida, CMV, ADV, VZV, HSV, Toxoplasma). Five of six haploidentical transplant recipients who received Ta1 are alive and disease free at a median follow-up of 10 months after transplantation (range: 5-20). They experienced only a single nonlethal infectious episode and one patient developed fatal immune hemolytic anemia. At this very early stage of the clinical trial, we conclude Ta1 administration is safe and may impact favorably on immune function. Larger numbers of patients and longer follow-up are, of course, needed to assess its impact on survival.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
FoxP3
+ regulatory T (Treg) cells are important mediators of peripheral tolerance, and deficiency of this population is associated with autoimmune inflammation and onset of acute lethal ...graft-vs.-host disease in transplantation. Type I IFN-producing plasmacytoid dendritic cells (pDC) are implicated in the induction and maintenance of tolerance and contribute to engraftment facilitation and prevention of graft-vs.-host disease after allogeneic hematopoietic stem cells transplantation (HSCT). Because host DC function is impaired during the immediate period post-transplant, the administration of donor DC may be useful for the educational program of recovering T cells. Distinct DC subsets could be derived from bone marrow (murine) or peripheral CD14
+ cell (human) cultures in the presence of either GM-CSF/IL-4 (myeloid DC) or FLT3-ligand (mainly pDC). The ability of either DC subset to induce Th1/Treg cell priming against
Aspergillus fumigatus as well as the relative contribution of murine DC subsets to antifungal priming upon adoptive transfer in hematopoietic transplanted mice with aspergillosis is not known. We found specialization and complementarity in priming and tolerization by the different DC subsets, with FL-DC fulfilling the requirement for (i) Th1/Treg antifungal priming; ii) tolerization toward alloantigens and (iii) diversion from alloantigen-specific to antigen-specific T cell responses in the presence of donor T lymphocytes. Interestingly, thymosin α1 (Tα1), known to modulate human pDC functions trough TLR9, affects mobilization and tolerization of pDC by activating the indoleamine 2,3-dioxygenase-dependent pathway, and this resulted in Treg development and tolerization. Thus, transplantation tolerance and concomitant pathogen clearance could be achieved through the therapeutic induction of antigen-specific Treg cells via instructive immunotherapy with pathogen- or TLR-conditioned donor DC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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