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TNFRSF13B /TACI and TNFRSF13C /BAFFR in B cell chronic lymphocytic leukemia

TNFRSF13B /TACI and TNFRSF13C /BAFFR in B cell chronic lymphocytic leukemia. Introduction. TACI: Receptor of BAFF and APRIL participates in: S urvival and differentiation of B cells T cell-independent immune respon-ses Antibody production Isotype switching Homeostasis of B cells

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TNFRSF13B /TACI and TNFRSF13C /BAFFR in B cell chronic lymphocytic leukemia

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  1. TNFRSF13B/TACI and TNFRSF13C/BAFFR in B cell chronic lymphocytic leukemia

  2. Introduction TACI: Receptor of BAFF and APRIL participates in: Survival and differentiation of B cells T cell-independent immune respon-ses Antibody production Isotype switching Homeostasis of B cells BAFF-R: Receptor of BAFF Expressed on naïve B cells triggering their survival and maturation Mackay et al, Cytokines & Growth Factor Reviews 2008

  3. Introduction TACI and BAFFR might participate in the survival of B-CLL cells, protecting them from apoptosis through NFκΒ activation Novak et al, Blood 2002 Hait et al., Immunology 2006 Jian et al., Medical Journal 2008

  4. Introduction Anti-TACI, anti-BAFF and anti-APRIL therapeutic approaches are now available, for the treatment of patients with autoimmune diseases and might be useful in patients with B-CLL • Phase I/II study of TACI-Ig to neutralize APRIL and BlyS (R) in patients with refractory or relapsed multiple myeloma or active previously-treated Waldenstrom’s macroglobuliemia. Rossi et al, Blood 2005 • Synthetic anti-BR3 antibodies that mimic BAFF binding and target both human and murine B cells. Lee et al, Blood 2006 • Phase I clinical study of Atacicept in patients with relapsed and refractory B-cell Non-Hodgkin’s Lymphoma. Ansell et al, Clin Cancer Res, 2008 • Ib trial of Atacicept, a recombinant protein binding BlyS and APRIL, in patients with chronic lymphocytic leukemia(B-CLL) Kofler et al, Leukemia 2011 • Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas. Guadagnoli et al, Blood 2011

  5. Aim of the study The determination of TNFRSF13B/TACI and TNFRSF13C/BAFFR expression on B-CLL cells and their contribution to the phenotype and the prognosis of the disease

  6. Materials & Methods 104 patients with B-CLL (M/F: 59/45, mean age: 68.5 y) 30 patients with low-grade NHL (M/F: 18/12, mean age: 77.3 y) & 145 healthy donors (M/F: 84/61, mean age: 67.8 y) Bone marrow Peripheral blood

  7. Materials & Methods • Hematologic, serologic and flow cytometric analyses (for diagnostic purposes), including in B-CLL a further analysis of the most powerful prognostic factors (ZAP-70, CD38 and IgH mutational status). • TACI and BAFFR protein expression was detected by flow cytometry using monoclonal antibodies (TACI clone 1a1, Abcam and BAFFR clone 11C1 Biolegend, respectively) in all samples. • TNFRSF13B and TNFRSF13C mRNA expression were estimated by qRT-PCRin 29 samples(19 with B-CLL, 8 with NHL and isolated B cells from 2 healthy donors).

  8. Materials & Methods • B-CLL cells exhibiting high or absent TACI, were stimulated by PKW (pokweed) 2.5 ng/mL, BAFF 1 μg/mL and APRIL 200 ng/mL and the apoptosis status was estimated by flow cytometry using an Annexin V-FITC/ 7-AAD (7-AAD) kit. • BAFF and APRIL serum levels were estimated by ELISA in 37 samples (16 with B-CLL, 11 with NHL and 10 healthy donors). • The statistical analysis was performed using the SPSS software ver.16.0.

  9. Results - 1 Variable TACI mRNA and protein expression on B-CLL cells TACI=55% TACI=90.1% TACI=2.1% BAFFR protein expression B-CLL cells normal B cells MFI=11 MFI=6

  10. Results - 2 Variable TACI mRNA and protein expression on B-CLL cells TACI=55% TACI=90.1% TACI=2.1% TACI expression (%) B-CLL NHL Healthy

  11. Results - 3 • TACI expression was not • asso-ciated with (p>0.05): • the presence of autoimmunity, • hypogammaglobulinemia, • monoclonal gammapathy, • the infection risk and • the known prognostic factors of B-CLL Low TACI Medium TACI High TACI hypermutation status ≤ 98% good prognosis CD38 > 20% bad prognosis

  12. Results - 4 TACI protects B-CLL cells from apoptosis CONTROL BAFF APRIL Late apoptotic&dead Late apoptotic&dead Late apoptotic&dead TACI=2.1% alive Early apoptotic alive Early apoptotic alive Early apoptotic CONTROL BAFF APRIL TACI=50.1% Late apoptotic&dead Late apoptotic&dead Late apoptotic&dead alive Early apoptotic alive Early apoptotic alive Early apoptotic

  13. Results - 5 BAFFR_MFI B-CLL NHL Healthy Normal B cells BCLL cells BCLL cells At the relapse of the disease

  14. Results - 6 Serum BAFF was lowand APRIL high in the majority of B-CLL patients compared to NHL patients and healthy donors Soluble BAFF levels was low to undetectable in B-CLL patients. Kreuzaler et al, J Immunol 2012 APRIL serum levels predict time to first treatment in patients affected by B- cell chronic lymphocytic leukemia. Tecchio et al, Eur. J. Haematol 2011

  15. Conclusions • TACI expression is: • low in the majority of B-CLL patients • not associated with disease prognosis • accompanied by very low or absent serum BAFF and high serum APRIL levels • BAFFR MFI expression is: • low in the B-CLL and NHL patients These findings should be taken into account in the case of anti-TACI and anti-BAFFR therapeutic approaches.

  16. THANK YOU

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