Aspergillus and cytomegalovirus are major causes of morbidity/mortality after haploidentical hematopoietic transplantation. The high degree of mismatching makes cell immunotherapy impossible as it would result in lethal graft-versus-host disease (GvHD). We generated large numbers of donor T-cell clones specific for Aspergillus or cytomegalovirus antigens. We identified clones potentially responsible for causing GvHD by screening them for cross-reactivity against recipient mononuclear cells. Non-recipient reactive, pathogen-specific clones were infused soon after transplantation. They were CD4+ and produced high levels of interferon-gamma and low levels of interleukin-10. In 46 control transplant recipients who did not receive adoptive therapy, spontaneous pathogen-specific T cells occurred in low frequency 9 to 12 months after transplantation and displayed a non-protective low interferon-gamma/high interleukin-10 production phenotype. In the 35 recipients who received adoptive therapy, one single infusion of donor alloantigen-deleted, pathogen-specific clones in the dose range of 10(5) to 10(6) cells/kg body weight did not cause GvHD and induced high-frequency T-cell responses to pathogens, which exhibited a protective high interferon-gamma/low interleukin-10 production phenotype within 3 weeks of infusion. Frequencies of pathogen-specific T cells remained stable over time, and were associated with control of Aspergillus and cytomegalovirus antigenemia and infectious mortality. This study opens new perspectives for reducing infectious mortality after haploidentical transplantations.
"Aspergillus fumigatus is an ubiquitous mold that can cause distinct modes of pathology: invasive aspergillosis (IA) and allergic bronchopulmonary aspergillosis (ABPA) in clinical situations such as neutropenia, immune suppression and chronic obstructive lung disease. In these cases, impaired lung immunity and subsequent fungal infections are accompanied with insufficient Th1 (IA)20, 21 and overwhelming Th2 (ABPA) responses, respectively.22, 23 Foxp3+ nTreg as well as Foxp3+ iTreg have been demonstrated to be essential for the induction of protective tolerance to the fungus in mice24 and humans25 by inhibition of overwhelming effector Th1/Th2 cell responses at late stages of experimental IA24, 26 and in ABPA patients.25 "
[Show abstract][Hide abstract] ABSTRACT: Unlike induced Foxp3(+) regulatory T cells (Foxp3(+) iTreg) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity. We identified Crf-1/p41-specific latent-associated peptide(+) Tr1 cells in healthy humans and mice after vaccination with Crf-1/p41+zymosan. These cells produced high amounts of interleukin (IL)-10 and suppressed the expansion of antigen-specific T cells in vitro and in vivo. In mice, in vivo differentiation of Tr1 cells was dependent on the presence of the aryl hydrocarbon receptor, c-Maf and IL-27. Moreover, in comparison to Tr1 cells, Foxp3(+) iTreg that recognize the same epitope were induced in an interferon gamma-type inflammatory environment and more potently suppressed innate immune cell activities. Overall, our data show that Tr1 cells are involved in the maintenance of antifungal immune homeostasis, and most likely play a distinct, yet complementary, role compared with Foxp3(+) iTreg.Immunology and Cell Biology advance online publication, 13 May 2014; doi:10.1038/icb.2014.34.
"Given high degree of mismatching makes cell immunotherapy impossible, Perruccio et al.  improved the immune recovery after myeloablative haploidentical SCT by the infusion of nonalloreactive clones specific for CMV and Aspergillus. Within 3 weeks of the immunotherapy infusion, CMV-specific CD4+ T cell clones were 404 ± 124 per 106 cells, and IFN-γ-producing CMV-specific CD8+ cells were detected in normal frequencies. "
[Show abstract][Hide abstract] ABSTRACT: Cytomegalovirus (CMV) infection and delayed immune reconstitution (IR) remain serious obstacles for successful haploidentical stem cell transplantation (haplo-SCT). CMV-specific IR varied according to whether patients received manipulated/unmanipulated grafts or myeloablative/reduced intensity conditioning. CMV infection commonly occurs following impaired IR of T cell and its subsets. Here, we discuss the factors that influence IR based on currently available evidence. Adoptive transfer of donor T cells to improve CMV-specific IR is discussed. One should choose grafts from CMV-positive donors for transplant into CMV-positive recipients (D+/R+) because this will result in better IR than would grafts from CMV-negative donors (D-/R+). Stem cell source and donor age are other important factors. Posttransplant complications, including graft-versus-host disease and CMV infection, as well as their associated treatments, should also be considered. The effects of varying degrees of HLA disparity and conditioning regimens are more controversial. As many of these factors and strategies are considered in the setting of haplo-SCT, it is anticipated that haplo-SCT will continue to advance, further expanding our understanding of IR and CMV infection.
Research Journal of Immunology 04/2014; 2014:631951. DOI:10.1155/2014/631951
"However, removal from the graft of mature T cells that, in HLA-matched transplants, are mainly responsible for protection from severe infections resulted in a state of immune deficiency for several months after transplantation. In order to overcome, at least in part, this major disadvantage, the adoptive infusion of T cell lines or clones specific for common life-threatening pathogens, including cytomegalovirus, Epstein–Barr virus, adenovirus, and Aspergillus, has been applied successfully in pilot trials (83–85). Another possible consequence of the extensive T cell depletion was a higher rate of leukemia relapses. "
[Show abstract][Hide abstract] ABSTRACT: Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class I-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection.
Frontiers in Immunology 03/2014; 5:87. DOI:10.3389/fimmu.2014.00087
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