Local intragraft humoral immune responses in chronic lung allograft dysfunction.

Background: Donor human leukocyte antigen (HLA)-specific antibodies (DSA) and non-HLA antibodies can cause allograft injury, possibly leading to chronic lung allograft dysfunction (CLAD) after lung transplantation. It remains unclear whether these antibodies are produced locally in the graft or derived solely from circulation. We hypothesized that DSA and non-HLA antibodies are produced in CLAD lungs.

Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCs).

Donor Batf3 inhibits murine lung allograft rejection and airway fibrosis.

Chronic lung allograft dysfunction (CLAD) limits survival after lung transplantation. Noxious stimuli entering the airways foster CLAD development. Classical dendritic cells (cDCs) link innate and adaptive immunity and exhibit regional and functional specialization in the lung.

Recipient bone marrow-derived IL-17 receptor A-positive cells drive allograft fibrosis in a mouse intrapulmonary tracheal transplantation model.

IL-17A is implicated in the pathogenesis of chronic lung allograft dysfunction, which limits survival after lung transplantation. While many cells express the IL-17 receptor A (IL-17RA) which is the main receptor for IL-17A, the cellular targets of IL-17A in development of post-transplant fibrosis are unknown. The purpose of this study was to determine whether IL-17RA expression by donor or recipient structural or bone marrow (BM) cells is required for the development of allograft fibrosis in a mouse intrapulmonary tracheal transplantation (IPTT) model.

delivery of regulatory T-cells for control of alloimmune priming in the donor lung.

Background: Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T-cells (Tregs) are being studied as a cellular therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern.

A B cell-dependent pathway drives chronic lung allograft rejection after ischemia-reperfusion injury in mice.

Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplant (LT). Ischemia-reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H-2 ] → C57BL/6 [B6, H-2 ]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage.

Epithelial cell death markers in bronchoalveolar lavage correlate with chronic lung allograft dysfunction subtypes and survival in lung transplant recipients-a single-center retrospective cohort study.

Chronic lung allograft dysfunction (CLAD) remains the leading cause of late death after lung transplantation. Epithelial injury is thought to be a key event in the pathogenesis of CLAD. M30 and M65 are fragments of cytokeratin-18 released specifically during epithelial cell apoptosis and total cell death, respectively.

Sequential broncho-alveolar lavages reflect distinct pulmonary compartments: clinical and research implications in lung transplantation.

Background: Bronchoalveolar lavage (BAL) has proven to be very useful to monitor the lung allograft after transplantation. In addition to allowing detection of infections, multiple BAL analytes have been proposed as potential biomarkers of lung allograft rejection or dysfunction. However, BAL collection is not well standardized and differences in BAL collection represent an important source of variation.

NKG2D regulates production of soluble TRAIL by ex vivo expanded human γδ T cells.

Soluble TRAIL (sTRAIL) can be produced by myeloid-derived cells to kill cancer cells. Whether this mechanism is used by T cells, and if so, how sTRAIL production is regulated, remains unclear. Our previous studies showed that ex vivo expanded human γδ T cells express TRAIL and NK receptor group 2 (R2), member D (NKG2D), and possess potent anticancer activities both in vitro and in vivo.

FcRγ promotes T cell apoptosis in Fas-deficient mice.

Deficiency of Fas or its ligand leads to lymphocyte accumulation, lymphadenopathy, splenomegaly, and autoimmunity in mice and humans. Although the Fas pathway is important for limiting the number of peripheral T cells, inactivation of other pro-apoptotic molecules can also perturb T cell homeostasis independently of and/or in concert with Fas deficiency. Here, we show that combined deficiency of Fas and the Fc receptor common γ signaling chain (FcRγ) results in worsened T cell accumulation in comparison with mice lacking Fas alone, with a particularly marked increase in the number of TCRαβ(+)CD4(-)CD8(-) double negative (DN) T cells.

Autocrine IFNγ controls the regulatory function of lymphoproliferative double negative T cells.

TCRαβ(+) CD4(-)CD8(-)NK(-) double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4(+) T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation.

Human Vδ1-T cells regulate immune responses by targeting autologous immature dendritic cells.

Recent studies suggest that tissue resident Vδ1-T cells may downregulate immune responses in human beings. However, the function of peripheral blood Vδ1-T cells and their mechanisms of action remain largely unknown because of their limited numbers and the difficulties encountered in expanding these cells. In this study, we provide direct evidence demonstrating that peripheral human Vδ1-T cells can abrogate adaptive immune responses by direct killing of autologous dendritic cells through a perforin-mediated pathway.

Adoptive immunotherapy of cancer using ex vivo expanded human gammadelta T cells: A new approach.

gammadelta T cells can be an option for adoptive immunotherapy of cancer. The major obstacle to clinical application of gammadelta T cells is their low number and lack of a reliable method to expand them consistently and efficiently. We were able to expand gammadelta T cells with high purity in all donors regardless of their starting repertoire of gammadelta T cells.

Cutting edge: in vivo trogocytosis as a mechanism of double negative regulatory T cell-mediated antigen-specific suppression.

Recent data have demonstrated that treatment with alphabeta-TCR(+)CD3(+)CD4(-)CD8(-)NK1.1(-) double negative (DN) regulatory T cells (Tregs) inhibits autoimmune diabetes and enhances allotransplant and xenotransplant survival in an Ag-specific fashion. However, the mechanisms whereby DN Tregs suppress Ag-specific immune responses remain largely unknown.

IL-10 induces regulatory T cell apoptosis by up-regulation of the membrane form of TNF-alpha.

Numerous studies have demonstrated the role of regulatory T (Treg) cells in peripheral tolerance. Nevertheless, how the survival and death of Treg cells is controlled is largely unknown. In this study, we investigated the mechanisms involved in regulating the homeostasis of a subset of Ag-specific alphabetaTCR+ CD4-CD8- double negative (DN) Treg cells.