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Ricostituzione Immune e Chimerismo post-Trapianto

Ricostituzione Immune e Chimerismo post-Trapianto. Pathways of T-cell Reconstitution. Naive T cells. IL-7. Stem cells. Thymus. IL-15 IL-21. Memory T cells. Antigens. Mature T cells. Cytokines. Homeostatic peripheral expansion. T-cell reconstitution following SCT.

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Ricostituzione Immune e Chimerismo post-Trapianto

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  1. Ricostituzione Immune e Chimerismo post-Trapianto

  2. Pathways of T-cell Reconstitution Naive T cells IL-7 Stem cells Thymus IL-15 IL-21 Memory T cells Antigens Mature T cells Cytokines Homeostatic peripheral expansion

  3. T-cell reconstitutionfollowing SCT TREC/T cell diversity Early post transplant homeostatic proliferation expansion B cell Treg Infections TREC/T cell diversity Late Renewed Thymopoiesis B cell diversity Long-term immunity Infections Treg

  4. B-Cell Immune Reconstitution Following SCT • Prolonged low levels of circulating B cell numbers • Deficit of mature B cells • Reduced ability to undergo somatic hypermutation: - maturation arrest at the naive stage due to insufficient CD4+ help for isotype switching - environmental defects

  5. Is Immune Reconstitution better after RIC as compared to myeloablative SCT? • Persistence of host residual mature T cell (mixed chimerism) immunologically competent • Theoretical preservation of thymic function

  6. Is immune Reconstitution better after RIC as compared to myeloablative SCT?(factors against) • Advanced age of patients included in the studies • Majority of patients failed autologous SCT • Use of Campath or ATG have a deleterius effect on the thymic indipendent pathway of lymphocyte reconstitution • Use of Rituximab before and after allo-SCT impairs long-term B-cell reconstitution

  7. Methods for Evaluating T-cell IR • Immunophenotype analysis • CDR3 spectratyping: RT-PCR amplification of TCR transcripts across CDR3 region • T cell Receptor Excision Circles (TREC): real-time PCR • Antigen specific responses: intracellular cytokine flow cytometry analysis and/or upregulation of activation markers, cytokine secretion assay

  8. Methods for Evaluating IR CDR3 Spectratyping N-D-N TCRB-J TCRB constant TCRB variable • No consensus have been achieved to the most appropriate way to report this data • TCR spectratype might be influenced by T cell chimerism

  9. T-cell Receptor Excision Circles (TREC) TREC levels are influenced by kinetics of T-cell proliferation and apoptosis

  10. B-cell Immune Reconstitution VH2D VH3D VH4aD VH1D VH4bD VH5D VH6D VH7D

  11. Antigen Specific Responses: upregulation of CD137 after exposition to CMV antigen Unstimulated CMV antigen Superantigen

  12. Factors affecting Immune Reconstitution • Patient age • Stem cell source and ex-vivo manipulation • Type of Donor • Type of Conditioning • Number of CD34+ and CD3+ (graft composition) • GVHD (induce thymic dysplasia, failure of elimination of alloreactive T cells) • Chimerism (complete donor chimerism had a correlation with a complete normalization of T-cell repertoire, Wu et al Blood 2000)

  13. RIC vs MAC(matched sibling)

  14. RIC vs MAC(matched sibling) NM MA All but threepatients in the non- myeloablative group engrafted with mixed T cell chimerism

  15. RIC vs MAC

  16. RIC vs MAC

  17. TBI 2Gy/Flu and Immune Reconstitution

  18. TBI 2Gy/Flu and Immune ReconstitutionTREC analysis

  19. FC+R and allogeneic SCT in relapsed follicular lymphomas N=47 patients, Grade 3 (21%), Previous therapy with Rituximab combinations: 74% Status of disease at Tx: 38% CR, 62% PR N= 45 (96%) underwent allogeneic SCT from HLA identical sibling R* Fludara 30 mg/m2 R R* R* -6 -5 -4 -3 +1 +3 +6 +8 -13 0 R= Rituximab 375mg/m2 R*=Rituximab 1000 mg/m2 CTX 750 mg/m2 MTX 5 mg/m2 tacrolimus until 6 months

  20. B-cell Immune Reconstitution CD19+ IgG IgA IgM Khouri IF, Blood 2008

  21. CSA 1mg/kg -> 2 mg/kg MTX MTX MTX Treatment Plan Thiotepa 10mg/kg Fludara 30 mg/ms CTX 30 mg/kg CAMPATH-1H 7.5 mg/ms or 15 mg/ms -6 -4 -3 -2 -1 0 +1 +3 +6 +30 +60 +70 +90 +120 +150 +180 Allo-PBSC Objectives of the study: - acute GVHD incidence - TRM

  22. Reduced-intensity conditioning(thiotepa 10 mg/kg, flu 60 mg/m2, CTX 60 mg/kg) 83% 94% 97%

  23. RIC-Campath and IR CD4+ CD8+ DC1 myeloid DC2 plasmacytoid

  24. RIC-Campath and IR *percentage of Vβ families with a normal complexity (≥ 5 bands)

  25. RIC-Campath and IR

  26. Effect of RIC with HD-Campath and Flu/Melfalan • 19 patients with MM • 11 allografted from matched sibling, 8 from MUD • 16 received DLI at 6 months after allo, 2 before the 6 months • Median value of CD4+ 150/µcl at 12 months • In the first 6 months TCR spectratyoing profiles were low median 55% (normal range 69%-82%). D’sa B Journal Hematology 2003

  27. Immune Reconstitution after RIC • Few comparative data with conventional transplants • Immunity after RIC seems to be better during the early period after SCT, no difference at 1 year • De novo production by the thymus can occur also in older patients after non-myeloablative SCT

  28. Approaches to reconstituting immunity T cell precursors in allogeneic SCT: Alloreactive > antiviral > antitumor • Unmanipulated DLI: risk of GVHD • Generation of antigen-specific T cells: require GMP facilities and are very complex • CD8-depleted DLIs • Thymic interventions: androgen blockade, cytokines (IL-7)

  29. Effect of CD8-depleted DLIs

  30. Effect of CD8-depleted DLIs

  31. Department of Hematology P. Corradini R. Milani V. Montefusco L. Farina N. Frungillo F. Spina M. Morelli S. Mappa S. Piva Molecular Laboratory C. Carniti A. Raganato A. Vendramin S. Di Terlizzi Aknowledgments

  32. Hematology - BMT Unit Istituto Nazionale dei Tumori University of Milano P. Corradini, A. Dodero R. Milani, V. Montefusco, F. Zallio, L. Farina Aknowledgments Dept. of Hematology University of Verona F. Benedetti, G. Pizzolo Dept. of Hematology University of Udine F. Patriarca, R. Fanin Dept. of Hematology University of Torino C. Tarella, M. Boccadoro Dept. of Medical Oncology Istituto Nazionale Tumori University of Milano A.M. Gianni, L. Devizzi Dept. of Hematology Ospedali Riuniti, Bergamo A. Rambaldi T. Barbui Dept. of Hematology University of Milano-Bicocca E. Pogliani Dept. of Hematology University of Ancona A. Olivieri, P. Leoni Dept. of Hematology Cervello Hospital, Palermo S. Mirto, R. Scimè, A. Santoro Dept. of Hematology University of Bologna G. Bandini, F. Bonifazi Dept of Hematology San Camillo Hospital, Roma A. Locasciulli, I. Majolino Dept. of Hematology University of Modena F.Narni Dept. of Hematology University of Cuneo N. Mordini Dept. of Hematology University of Genova A.Bacigalupo Dept. of Hematology University of Pescara P. Di Bartolomeo Dept. of Hematology H. S. Raffaele , Milano F. Ciceri, M. Bregni

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