Mast cells contribute to the induction of ocular mucosal alloimmunity

Beyond their historical role as the effector cells in allergic disorders, mast cells have been implicated in regulating both innate and adaptive immune responses. Possessing considerable functional plasticity, mast cells are abundant at mucosal surfaces, where the host and external environments interface. The purpose of this study was to evaluate the contribution of mast cells to allograft rejection at the ocular surface. Using a well‐characterized murine model of corneal transplantation, we report that mast cells promote allosensitization. Our data show mast cell frequencies and activation are increased following transplantation. We demonstrate that mast cell inhibition (a) limits the infiltration of inflammatory cells and APC maturation at the graft site; (b) reduces allosensitization and the generation of Th1 cells in draining lymphoid tissues; (c) decreases graft infiltration of alloimmune‐inflammatory cells; and (d) prolongs allograft survival. Our data demonstrate a novel function of mast cells in promoting allosensitization at the ocular surface.

[1]  W. Foulsham,et al.  Mast Cells Initiate the Recruitment of Neutrophils Following Ocular Surface Injury , 2018, Investigative ophthalmology & visual science.

[2]  W. Foulsham,et al.  Mesenchymal Stromal Cells Inhibit Neutrophil Effector Functions in a Murine Model of Ocular Inflammation , 2018, Investigative ophthalmology & visual science.

[3]  R. Dana,et al.  Proangiogenic Function of T Cells in Corneal Transplantation , 2017, Transplantation.

[4]  R. Dana,et al.  T Cell–Derived Granulocyte-Macrophage Colony-Stimulating Factor Contributes to Dry Eye Disease Pathogenesis by Promoting CD11b+ Myeloid Cell Maturation and Migration , 2017, Investigative ophthalmology & visual science.

[5]  M. Alegre,et al.  Antigen Presentation in Transplantation. , 2016, Trends in immunology.

[6]  D. Underhill,et al.  Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan , 2016, Cell.

[7]  R. Dana,et al.  Alloimmunity and Tolerance in Corneal Transplantation , 2016, The Journal of Immunology.

[8]  R. Dana,et al.  In Vivo Expansion of Regulatory T Cells by Low-Dose Interleukin-2 Treatment Increases Allograft Survival in Corneal Transplantation , 2016, Transplantation.

[9]  Yangqiu Li,et al.  Mast Cells Participate in Corneal Development in Mice , 2015, Scientific Reports.

[10]  R. Dana,et al.  Ocular surgical models for immune and angiogenic responses. , 2015, Journal of biological methods.

[11]  S. Bulfone-Paus,et al.  Mast Cells as Regulators of T Cell Responses , 2015, Front. Immunol..

[12]  S. Chauhan,et al.  Mesenchymal stem cells home to inflamed ocular surface and suppress allosensitization in corneal transplantation. , 2014, Investigative ophthalmology & visual science.

[13]  Sakuo Yamada,et al.  Does β-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of β-Hexosaminidase in Mast Cell Granules , 2014, The Journal of Immunology.

[14]  R. Dana,et al.  CCL-21 Conditioned Regulatory T Cells Induce Allotolerance through Enhanced Homing to Lymphoid Tissue , 2014, The Journal of Immunology.

[15]  S. Galli,et al.  Mast cells suppress murine GVHD in a mechanism independent of CD4+CD25+ regulatory T cells. , 2013, Blood.

[16]  D. Voehringer Protective and pathological roles of mast cells and basophils , 2013, Nature Reviews Immunology.

[17]  J. Gommerman,et al.  Fine-tuning of dendritic cell biology by the TNF superfamily , 2012, Nature Reviews Immunology.

[18]  R. M. Wijngaard,et al.  Intestinal mast cells in gut inflammation and motility disturbances , 2012 .

[19]  L. Turka,et al.  Innate immunity in transplant tolerance and rejection , 2011, Immunological reviews.

[20]  D. Bentrem,et al.  The significant role of mast cells in cancer , 2011, Cancer and Metastasis Reviews.

[21]  A. Gilfillan,et al.  Regulation of mast cell responses in health and disease. , 2011, Critical reviews in immunology.

[22]  A. Liston,et al.  Regulatory T Cells , 2011, Methods in Molecular Biology.

[23]  H. Kuehn,et al.  Measuring Mast Cell Mediator Release , 2010, Current protocols in immunology.

[24]  Ashley M. Miller,et al.  Mast cells express IL-17A in rheumatoid arthritis synovium. , 2010, Journal of immunology.

[25]  R. Dana,et al.  Role of CCR7 in facilitating direct allosensitization and regulatory T-cell function in high-risk corneal transplantation. , 2010, Investigative ophthalmology & visual science.

[26]  A. Magil Monocytes/macrophages in renal allograft rejection. , 2009, Transplantation reviews.

[27]  R. Dana,et al.  Autoimmunity in Dry Eye Is Due to Resistance of Th17 to Treg Suppression1 , 2009, The Journal of Immunology.

[28]  R. Dana,et al.  Levels of Foxp3 in Regulatory T Cells Reflect Their Functional Status in Transplantation1 , 2009, The Journal of Immunology.

[29]  A. Leonardi,et al.  Allergy and the eye , 2008, Clinical and experimental immunology.

[30]  D. Vignali,et al.  How regulatory T cells work , 2008, Nature Reviews Immunology.

[31]  M. Loebe,et al.  The role of mast cells after solid organ transplantation. , 2008, Transplantation.

[32]  G. Freeman,et al.  The Function of Donor versus Recipient Programmed Death-Ligand 1 in Corneal Allograft Survival1 , 2007, The Journal of Immunology.

[33]  S. Thakurdas,et al.  The Mast Cell-restricted Tryptase mMCP-6 Has a Critical Immunoprotective Role in Bacterial Infections* , 2007, Journal of Biological Chemistry.

[34]  P. Libby,et al.  Mast cells promote atherosclerosis by releasing proinflammatory cytokines , 2007, Nature Medicine.

[35]  David C. Gondek,et al.  Mast cells are essential intermediaries in regulatory T-cell tolerance , 2006, Nature.

[36]  M. Tsai,et al.  Mast Cells Enhance T Cell Activation: Importance of Mast Cell Costimulatory Molecules and Secreted TNF1 , 2006, The Journal of Immunology.

[37]  M. Dana,et al.  Early ocular chemokine gene expression and leukocyte infiltration after high-risk corneal transplantation. , 2005, Molecular vision.

[38]  M. Tsai,et al.  Mast cells in the development of adaptive immune responses , 2005, Nature Immunology.

[39]  M. Kaliner,et al.  Cromolyn Sodium: Fitting an Old Friend into Current Asthma Treatment , 2005, The Journal of asthma : official journal of the Association for the Care of Asthma.

[40]  M. Tsai,et al.  Mast cells as "tunable" effector and immunoregulatory cells: recent advances. , 2005, Annual review of immunology.

[41]  Philip F Halloran,et al.  Immunosuppressive drugs for kidney transplantation. , 2004, The New England journal of medicine.

[42]  M. Dana,et al.  Relevance of the Direct Pathway of Sensitization in Corneal Transplantation Is Dictated by the Graft Bed Microenvironment1 , 2004, The Journal of Immunology.

[43]  S. Holgate,et al.  NF-κB and TNF-α: A Positive Autocrine Loop in Human Lung Mast Cells? , 2002, The Journal of Immunology.

[44]  M. Arock,et al.  The role of mast cells in host defense and their subversion by bacterial pathogens. , 2002, Trends in immunology.

[45]  Susan J Wilson,et al.  NF-kappa B and TNF-alpha: a positive autocrine loop in human lung mast cells? , 2002, Journal of immunology.

[46]  N. Philpott,et al.  TNF-α-dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[47]  D. Lúdvíksdóttir,et al.  Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group. , 2000, American journal of respiratory and critical care medicine.

[48]  J. Streilein,et al.  ORTHOTOPIC CORNEAL TRANSPLANTATION IN MICE—EVIDENCE THAT THE IMMUNOGENETIC RULES OF REJECTION DO NOT APPLY , 1992, Transplantation.