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Effective Combination of Syngeneic HCT with CRCL Vaccination to Treat BCR-ABL+ Leukemia and CD4+CD25+FoxP3+ Regulatory T Cells Suppress Mycobacterium Tuberculosis Immunity in Patients with Active DiseaseChen, Xinchun January 2006 (has links)
Chronic myelogenous leukemia (CML) is a clonal hematopoetic stem cell disorder characterized by proliferation of cells expressing BCR-ABL fusion protein. In the BCR-ABL+ leukemia murine model, 12B1, we explored the therapeutic applicability of chaperone-rich cell lysate (CRCL) in the context of syngeneic hematopoietic cell transplantation (HCT) to treat pre-existing leukemia. Our results demonstrate that tumor growth is significantly delayed in mice receiving syngeneic HCT from 12B1 tumor CRCL immunized donors compared to animals receiving HCT from non-immunized donors. CRCL immunization post-immune HCT further hindered tumor growth when compared to immune HCT without post-transplant vaccination. The magnitude of the immune response was consistent with the anti-tumor effects observed in vivo. We also demonstrated that cured mice had developed long-term tumor specific immunity against 12B1 tumor cells. In addition, we documented that both T cells and NK cells contributed to the anti-tumor effect of CRCL vaccination as depletion of either subset hampered tumor growth delay. Thus, our results suggest that CRCL represents a promising vaccine capable of generating specific immune responses. This anti-tumor immunity can be effectively transferred to a host via HCT and further enhanced post-HCT with additional tumor CRCL immunizations.CD4+CD25+ regulatory T cells (Treg) play a central role in the prevention of autoimmunity and in the control of immune responses by down-regulating the function of effector CD4+ or CD8+ T cells. The role of Treg in Mycobacterium tuberculosis infection and persistence is inadequately documented. Therefore, the current study was designed to determine whether CD4+CD25+ FoxP3+ regulatory T cells may modulate immunity against human tuberculosis (TB). Ourresults indicate that the number of CD4+CD25+FoxP3+ Treg increases in the blood or at the site of infection in active TB patients. The frequency of CD4+CD25+FoxP3+ Treg in pleural fluid inversely correlates with local MTB-specific immunity(p<0.002). These CD4+CD25+FoxP3+ T lymphocytes isolated from the blood and pleural fluid are capable of suppressing MTB-specific IFN-γ and IL-10 production in TB patients. Therefore, CD4+CD25+FoxP3+ Treg expanded in TB patients suppress Mycobacterium tuberculosis immunity and may therefore contribute to the pathogenesis of human TB.
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Γονιδιωματική αστάθεια στο επιθήλιο μετά από αλλογενή μεταμόσχευση αιμοποιητικών κυττάρων : μηχανισμός και κλινική σημασίαΘέμελη, Μαρία 15 March 2012 (has links)
Υποθέσαμε ότι το χρόνιο ιστικό στρες που προκαλείται από τις αλλοαντιδράσεις μετά από αλλογενή Μεταμόσχευση Αιμοποιητικών Κυττάρων (άλλο-ΜΑΚ) μπορεί να επάγει την εμφάνιση γονιδιωματικής αστάθειας (GI) στους επιθηλιακούς ιστούς. Για αυτό, 176 στοματικά επιχρίσματα από 71 ασθενείς μετά από άλλο-ΜΑΚ αναλύθηκαν για την ανίχνευση αστάθειας μικροδορυφορικών αλληλουχιών (microsatellite instability-MSI). Tα αποτελέσματα συσχετίσθηκαν με κλινικές παραμέτρους. Σε ένα in vitro σύστημα ανίχνευσης μεταλλάξεων ελέγξαμε την υπόθεση ότι οι αλλοαντιδράσεις μπορεί να επάγουν τη GI στην κυτταρική σειρά HaCaT. Ανιχνεύθηκε MSI στο 52% των αλλομεταμοσχευμένων ασθενών ενώ δεν ανιχνεύθηκε MSI σε ασθενείς μετά από αυτόλογη ΜΑΚ και υγιείς εθελοντές. Βρέθηκε σημαντική συσχέτιση της εμφάνισης MSI με την ηλικία του ασθενούς και του δότη, τη μεταμόσχευση από γυναίκα σε άνδρα και τον αριθμό CD34+ κυττάρων στο μόσχευμα. Οι ασθενείς με ιστορικό σοβαρού βαθμού αντίδρασης μοσχεύματος εναντίον ξενιστή είχαν μεγαλύτερο σχετικό κίνδυνο για εμφάνιση MSI. Δευτεροπαθής κακοήθεια διαγνώσθηκε σε 5 από τους MSI+ ενώ μόνο σε ένα από τους MSI- ασθενείς. Στο in-vitro σύστημα ανίχνευσης GI παρατηρήθηκε σημαντική επαγωγή μεταλλάξεων και βλάβης του DNA μετά από επώαση των HaCaT κυττάρων με Μεικτή Λεμφοκυτταρική Καλλιέργεια (MLC) ενώ η επίδραση με κυτταροκίνες, υπερκείμενο MLC ή ενεργοποιημένα με PHA περιφερικά μονοπύρηνα κύτταρα δεν προκάλεσε την επαγωγή GI. Τα αποτελέσματά μας υποδεικνύουν τη συμμετοχή των ενεργών ριζών οξυγόνου στον υποκείμενο μηχανισμό. Οι in vivo και in vitro μελέτες μας επιβεβαιώνουν ότι παράγοντες που ενέχονται στο αλλοαντιδραστικό μικροπεριβάλλον μετά από άλλο-ΜΑΚ μπορεί να προκαλέσουν GI στο επιθήλιο. Η κατανόηση του υποκείμενου μηχανισμού μπορεί να αναδείξει νέους βιοδείκτες και θεραπευτικούς στόχους. / We hypothesized that chronic tissue stress due to interaction of alloreactive donor cells with host epithelium after allogeneic hematopoietic cell transplantation (allo-HCT) may cause genomic alterations. We therefore analysed 176 buccal samples obtained from 71 unselected allo-transplanted patients for microsatellite instability (MSI). MSI was observed in 52% of allo-transplanted patients but never in 31 healthy or auto-transplanted controls. The patient age, the donor age, a female-to-male transplantation and a low number of CD34+ cells in the graft were significantly correlated with genomic instability. There was a trend for increasing risk of MSI for patients who experienced severe graft-versus-host-disease. Secondary malignancy was diagnosed in 5 (14%) of the MSI+ and only in 1 (3%) MSI- patient. In an in-vitro model of mutation analysis we found significant induction of frameshift mutations and DNA strand breaks in HaCaT keratinocytes co-cultured with Mixed Lymphocyte Cultures (MLC) but not after their exposure to IFN-γ, TNF-α, TGF-β, MLC-supernatant, peripheral blood mononuclear cells (PBMC) or phytohemagglutinin stimulated PBMC. A ROS mediated mechanism is implicated. Our in-vivo and in-vitro data show that alloreactions after allo-HCT may induce genomic alterations in epithelium. Progress in understanding DNA damage and repair after allo-HCT can potentially provide molecular biomarkers and therapeutic targets.
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Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell MalignanciesTomaszewska, Agnieszka, Jagasia, Madan, Beohou, Eric, van der Werf, Steffie, Blaise, Didier, Kanfer, Edward, Milpied, Noel, Reményi, Péter, Ciceri, Fabio, Bourhis, Jean H., Chevallier, Patrice, Solano, Carlos, Socié, Gerard, Bruno, Benedetto, Rambaldi, Alessandro, Castagna, Luca, Kröger, Nicolaus, Corradini, Paolo, Afanasyev, Boris, Ladetto, Marco, Niederwieser, Dietger, Scheid, Christof, Sengeloev, Henrik, Kroschinsky, Frank, Yakoub-Agha, Ibrahim, Schoemans, Helene, Koenecke, Christian, Penack, Olaf, Peri´c, Zinaida, Greinix, Hildegard, Duarte, Rafael L., Basak, Grzegorz W. 24 March 2023 (has links)
Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens
for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell
malignancies, not only to improve disease control, but also to prevent graft-versus-host
disease (GVHD). There are no randomized prospective data to validate this practice,
although single center data and the CIBMTR analysis have shown promising results. We
aimed at validation of these findings in a large registry study. We conducted a
retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell
malignancies undergoing alloHCT (2001–2013) with either rituximab (R-RIC-9%) or nonrituximab
(RIC-91%) reduced intensity regimens respectively. Median age and median
follow up were 55 years (range 19.1–77.3) and 43.2 months (range 0.3–179.8),
respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including
1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%),
1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4°
(12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell
malignancies had no significant impact on major transplant outcome variables. Of note,
data on chronic GVHD was not available, limiting the conclusions that can be drawn from
the present study.
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Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantationKunadt, Desiree, Stasik, Sebastian, Metzeler, Klaus H., Röllig, Christoph, Schliemann, Christoph, Greif, Philipp A., Spiekermann, Karsten, Rothenberg-Thurley, Maja, Krug, Utz, Braess, Jan, Krämer, Alwin, Hochhaus, Andreas, Scholl, Sebastian, Hilgendorf, Inken, Brümmendorf, Tim H., Jost, Edgar, Steffen, Björn, Bug, Gesine, Einsele, Hermann, Görlich, Dennis, Sauerland, Cristina, Schäfer-Eckart, Kerstin, Krause, Stefan W., Hänel, Mathias, Hanoun, Maher, Kaufmann, Martin, Wörmann, Bernhard, Kramer, Michael, Sockel, Katja, Egger-Heidrich, Katharina, Herold, Tobias, Ehninger, Gerhard, Burchert, Andreas, Platzbecker, Uwe, Berdel, Wolfgang E., Müller-Tidow, Carsten, Hiddemann, Wolfgang, Serve, Hubert, Stelljes, Matthias, Baldus, Claudia D., Neubauer, Andreas, Schetelig, Johannes, Thiede, Christian, Bornhäuser, Martin, Middeke, Jan M., Stölzel, Friedrich 11 June 2024 (has links)
Background
The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).
Methods
Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.
Results
Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).
Conclusion
In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.
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