A comparison of gene transfer and antigen-loaded dendritic cells for the generation of CD4+ and CD8+ cytomegalovirus-specific T cells in HLA-A2+ and HLA-A2−

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Presentation transcript:

A comparison of gene transfer and antigen-loaded dendritic cells for the generation of CD4+ and CD8+ cytomegalovirus-specific T cells in HLA-A2+ and HLA-A2− donors Aaron E. Foster, Kenneth F. Bradstock, Uluhan Sili, Marina Marangolo, Cliona M. Rooney, David J. Gottlieb Biology of Blood and Marrow Transplantation Volume 10, Issue 11, Pages 761-771 (November 2004) DOI: 10.1016/j.bbmt.2004.05.011 Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Transduction of DCs with Ad5pp65GFP. DCs were incubated on day 5 with Ad5pp65GFP and analyzed on day 7 for the expression of GFP. DCs were gated by high forward and side scatter (A) and analyzed by comparing CD11c and GFP expression on nontransduced DCs (B) and Ad5pp65GFP-transduced DCs (C). Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Autologous mixed lymphocyte reaction with CMV-loaded DCs. DCs were analyzed for the ability to stimulate CMV-specific proliferation in a CMV-seropositive donor. (A) Proliferation of PBMCs stimulated with DCs that were mock-transduced, or transduced with Ad5GFP only or Ad5pp65GFP encoding pp65, and then used in a 5-day [3H]thymidine proliferation assay in quadruplicate. (B) Proliferation of PBMCs stimulated with DCs incubated with CMV lysate was compared with DCs loaded with control antigen and mock-loaded DCs. PBMCs and DCs were also compared for proliferation alone. *P < .05 against DCs loaded with control antigen. Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Tetramer expansion after stimulation with different CMV antigen types. The frequency of CD8+ tetramer+ T cells was compared after PBMCs from a CMV-seropositive donor were stimulated with DCs loaded with NLV peptide, Ad5pp65GFP, or CMV lysate. Unstimulated PBMCs are shown on the left, and CMV-specific T-cell cultures are shown at day 7 and 14 for their respective antigen types. Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Expansion of CMV-specific T cells from a single HLA-A2+ donor after stimulation with CMV-loaded DCs. Total cells (A) and total tetramer+ CD8+ T cells (B) were enumerated after 21 days in culture from HLA-A2+ donors (n = 3; donors 1, 2, and 5) after stimulation with DCs loaded with Ad5pp65GFP (•), CMV lysate (■), or NLV peptide (▴). Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Cytotoxicity of CMV-specific T-cell cultures against peptide-pulsed T2 target cells. (A) The cytotoxicity of CMV-specific T-cell cultures generated by DCs loaded with NLV peptide (triangles), Ad5pp65GFP (squares), and CMV lysate (circles) was tested against that of chromium-labeled T2 cells loaded with NLV peptide (closed symbols) or the irrelevant peptide VLQ (open symbols). (B) CMV-specific T-cell cultures stimulated with CMV lysate (•), Ad5pp65GFP (■), or NLV peptide (▴) were tested against T2 cells loaded with the CMV IE1 peptide VLE. Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 TCR Vβ analysis of CD4+ CMV-specific T cells. To assess whether CD4+ T cells expanded in response to CMV antigen stimulation, the CD4+ TCR Vβ frequency was analyzed on 2 donors (donor 1 and 2; panel 1 and 2, respectively) before CMV antigen stimulation and after 2 stimulations with DCs loaded with either Ad5pp65GFP or CMV lysate. Hashed boxes indicate expansion of similar CD4+ TCR Vβ regions between stimulating antigens. Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Production of IFN-γ by sorted CD4+ CMV-specific T cells. CD4+ CMV-specific T cells from donor 1 were sorted by flow cytometry and plated in microtiter plates in triplicate. DCs either loaded with CMV lysate transduced with Ad5pp65GFP or mock-loaded were then used to stimulate the T cells. IFN-γ production in response to stimulation was then measured by enzyme-linked immunosorbent assay. Both CMV lysate-stimulated and Ad5pp65GFP-stimulated T-cell cultures contained CD4+ T cells capable of recognizing CMV antigens. Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 8 Specificity of HLA-A2− CMV-specific T cells generated from Ad5pp65GFP-loaded and CMV lysate-loaded DCs. T-cell cultures from an HLA-A2− donor (donor 7) were assayed for CMV specificity by cytotoxicity and IFN-γ production by comparing the response to stimulation by DCs loaded with Ad5pp65GFP, CMV lysate, or control DCs. (A) Ad5pp65GFP-generated CMV-specific T cells lyse DC target cells transduced with Ad5pp65GFP (▴) and CMV lysate-pulsed DCs (■) but do not recognize Ad5GFP (□) or mock-pulsed DC (▵) target cells. (B) CMV lysate-generated CMV-specific T cells lyse both DC target cells transduced with Ad5pp65GFP (▴) and CMV lysate-pulsed DCs (■) but do not kill Ad5GFP (□) or mock-pulsed DC (▵) target cells. (C) CMV-specific T cells derived from an HLA-B35 donor (donor 6) after stimulation with Ad5pp65GFP, CMV lysate, or VFP (HLA-B35-restricted pp65 peptide) were tested for cytotoxicity against autologous chromium-labeled DC target cells pulsed with either VFP or irrelevant control peptide at a ratio of 50:1 effector/target cells. Biology of Blood and Marrow Transplantation 2004 10, 761-771DOI: (10.1016/j.bbmt.2004.05.011) Copyright © 2004 American Society for Blood and Marrow Transplantation Terms and Conditions