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High Expression of Fas Ligand on Cord Blood Dendritic Cells: a Possible Immunoregulatory Mechanism After Cord Blood Transplantation

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High Expression of Fas Ligand on Cord Blood Dendritic Cells: a Possible Immunoregulatory Mechanism After Cord Blood Transplantation High Expression of Fas Ligand on Cord Blood Dendritic Cells: A Possible Immunoregulatory Mechanism After Cord Blood Transplantation N. Naderi, S.M. Moazzeni, A.A. Pourfathollah, and K. Alimoghaddam ABSTRACT Background. Allogeneic cord blood transplantation is associated with less severe graft-versus-host disease (GVHD). Dendritic cells (DCs), as the most potent antigen- presenting cells of the immune system, play a central role in the development of GVHD. Because apoptosis induction is one of the known mechanisms that DCs use to regulate T-cell responses, we studied the immunostimulatory and apoptosis induction capacities of cord blood dendritic cells (CBDCs) and peripheral blood dendritic cells (PBDCs) to evaluate the mechanisms underlying the lower incidence of GVHD after cord blood transplantation. Presence of apoptosis-related markers Fas, Fas ligand (FasL), and CD40 and costimulatory molecules, along with the proportion of myeloid and lymphoid DCs subsets, were also measured on CBDCs and PBDCs. Methods. Fresh CBDCs and PBDCs were isolated from cord and peripheral mononu- clear cells as lineage-negative cells by using monoclonal antibodies against CD3, CD11b, CD14, CD16, CD19, CD56, CD34, and CD66b. DCs were cocultured with allogeneic T cells, and the effect of CBDCs and PBDCs on T-cell apoptosis and proliferation were determined through flow cytometric analysis and 3H-thymidine incorporation. Results. Our findings showed that CBDCs markedly augment apoptosis of CD3ϩ T-cells. FasL expression on CBDCs was significantly higher than on PBDCs. However, there was no difference between Fas expression on CBDCs and PBDCs. Moreover, CBDCs were poor stimulators of allogenic T cells in mixed leukocyte reaction compared with adult peripheral blood DCs. They also displayed decreased expression of HLA-DR and CD86 molecules. The ratio of lymphoid DCs (CD11cϪ, CD123ϩ)to myeloid DCs (CD11cϩ, CD123Ϫ) was also significantly higher in CBDCs compared with PBDCs. Conclusions. It seems that less severe GVHD after cord blood transplantation is due not only to a higher degree of immaturity of CBDCs, but also to delivery of apoptotic signals to the host T cells that recognize allo-MHC molecules on CBDCs in the early phase of immune response. llogeneic umbilical cord blood transplantation (CBT) responses following hematopoietic stem cell transplanta- A has been increasingly used recently for haematopoe- tion2 and induction of donor-specific hyporesponsiveness.3 itic reconstitution. Despite the existence of donor-receptor More recent studies have addressed the second role of DCs, HLA mismatches, lower incidence and severity of graft- versu-host disease (GVHD) is reported in cord blood 1 From the Immunology Department, Hormozgan University of allotransfusion (allo-CBT). Medical Sciences, Bandarabbas, Hormozgan, Iran. Dentritic cells (DCs) are thought to be critical in trigger- Address reprint requests to Dr. Nadereh Naderi, PhD, Hor- ing primary immune responses against novel antigens and mozgan University of Medical Sciences, P.O. Box 791969311, play a crucial role in induction of alloantigen-specific T-cell Bandarabbas, Hormozgan, Iran. © 2011 by Elsevier Inc. All rights reserved. 0041-1345/–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2011.10.040 Transplantation Proceedings, 43, 3913–3919 (2011) 3913 3914 NADERI, MOAZZENI, POURFATHOLLAH ET AL ie, the down-regulation of immune response.4 These appar- as TRANCE (TNF-related activation-induced cytokine) ently opposing functions of DCs are now verified to depend receptor23 and CD40,3 that counteract Fas molecule and on DCs maturation stages and subsets. Although cells from have important roles in increasing DC survival.24 Because it the dendritic family share many phenotypic and functional is largely unknown which of these T-cell–silencing factors is properties, the expression of certain cell surface markers involved in the less-severe GVHD following cord blood has led to recognition of substantial heterogeneity among transplantation, and to elucidate the role of apoptosis- them. DCs can be divided into at least 2 major subpopula- related mechanism in this phenomenon, our laboratory tions, ie, myeloid DCs and lymphoid DCs, with distinct examined this issue along with other variables that are likely to origin, phenotype, and function.5 Lymphoid DCs counter- affect DC efficacy, including phenotypic features, immune- act with myeloid DCs to prolong the allograft survival in stimulatory competence, and subset distribution of cord mice, regardless of their maturational status.6 blood DCs (CBDCs) compared with peripheral blood DCs Multiple mechanisms presumably collaborate to halt (PBDCs). DC-induced T-cell activation at both T-cell and DC levels. Apoptosis and Fas ligand (FasL) expression serve as com- MATERIALS AND METHODS mon and key events, leading to DC-induced immunological Blood Samples unresponsiveness.3,7 There is evidence that constitutive A total of 7 CB samples from healthy full-term newborns were expression of FasL on splenic DCs and bone marrow– obtained from the Hematology, Oncology, and Bone Marrow derived DCs may be involved in killing of activated Fas- Transplantation Research Center of Shariati Hospital (Tehran, ϩ 8,9 positive CD4 T cells. Iran) with the informed consents of the mothers. The CB units had The possibility that stimulation of Fas on the surface of a mean volume of 80 Ϯ 25 mL. In addition, 7 adult leukocyte– donor-specific T cells can protect tissue grafts from rejec- enriched buffy coats were obtained from the Iranian Blood Trans- tion was first explored by Bellgrau et al, who showed that fusion Organization with a mean volume of 32 Ϯ 8.5 mL. All FasL-expressing testicular allografts were accepted after samples were collected in heparin and immediately processed for transplantation, whereas grafts from FasL-deficient donor the immunophenotypic and functional studies. animals were normally rejected.10 Sharland et al and Car- roll et al have also highlighted the importance of apoptotic Cell Preparation deletion of antigen specific T cells in spontaneous accep- PBDCs and CBDCs were isolated according to a slightly modified tance of organ transplantation, such as liver allografts, and protocol described previously for PBDC separation.25 Briefly, the role of Fas and FasL molecules as key players in this blood mononuclear cells were isolated through Ficoll (Lym- phenomenon.11,12 phoprep, Axis-Shield, Norway) gradient centrifugation. CB and PB Indeed, the most profound form of tolerance that is mononuclear cells were then rosetted with S-2-aminoethyl isothiu- commonly observed in immune-privileged sites proceeds ronium bromide (Merck, Germany)–treated sheep red blood cells. via an initial activation phase.13 Expression of FasL in After depletion of rosetted cells using Ficoll gradient centrifuga- immune-privileged organs, including retinal cells of the eye tion to reduce the multiplicity of T cells, the nonrosetted fraction was stained with a cocktail of monoclonal antibodies designed to and Sertoli cells of the testis, has been proposed to initiate exclude lineage marker–positive cells, including anti-CD3 (clone a signaling cascade that leads to apoptotic cell death of UCHT1), anti-CD11b (clone ICRF44), anti-CD14 (clone M5E2), Fas-bearing invading T cells at an early stage of immune anti-CD16 (clone 3G8), anti-CD56 (clone B159), and anti-CD19 response and thereby contributes to spontaneous immune (clone HIB19). All antibodies were from immunoglobulin (Ig) G1 tolerance at the privileged sites.10,14 isotype and were prepared from BD Biosciences (USA). In case of On the other hand, there is another form of physiologic cord blood, anti-CD34 (clone 581; BD Biosciences) and anti- deletion of activated T cells, termed activation-induced cell CD66b (clone CLB-B13.9; Research Diagnostics, USA) were ϩ 15 included owing to the high frequency of CD34 stem cells and death (AICD). Fas and FasL are also involved in this ϩ later-stage apoptosis and could reduce immune response CD66b myeloid Ig-coated magnetic precursors in CB. The cells after prolonged T-cell activation, when T-cell clones expand were then incubated with goat antimouse beads (Dynal Biotech, Norway) followed by depletion of the labeled cells. The remaining and become redundant.12 cells were analyzed by flow cytometry to determine the DC purity. Massive activation-induced cell death (AICD) following To prepare T cells, the nonadherent floating cells were collected an initial brisk proliferation of donor T cells has been after 2 hours of mononuclear cell (MNC) culture and passed 16 reported recently in a murine model of GVHD. Other through a nylon wool column. Enriched T cells were obtained by studies demonstrate a delayed type increase in spontaneous depletion of nylon wool–adherent cells. The purity of T cells was apoptosis among peripheral blood T cells following alloge- determined by flow cytometry using antihuman CD3 monoclonal neic hematopoietic cell transplantation.17,18 antibody (clone UCTH1; BD Biosciences). Moreover, apoptosis of DCs appears to serve as another mechanism to decline T cell response.19 Fas expression has Flow Cytometric Analysis been detected on freshly prepared DCs from various tissues Triple staining was used for immunophenotyping of the DCs. 20,21 or short term DC lines. Matsue et al reported that Briefly, the cells were incubated with fluorescein isothiocyanate ligation of Fas on DCs by FasL on T cells is capable of (FITC)–or phycoerythim-conjugated F(ab=)2 goat antimouse
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