Basophils as modulators of humoral and cellular allo-immune responses
Final Report Abstract
We have proposed to address two main questions during the funding period. First, to analyse the role of basophils for chronic allograft rejection and second to analyse the contribution of hematopoietic collagen-producing cells, called fibrocytes, to allograft fibrosis. By depletion of basophils and the use of IL-4 deficient mice we could demonstrate for the first time an essential role of basophils for development of graft fibrosis as recently published in the Am. J. Transplant. Our experiments revealed that basophil-derived IL-4 is a main profibrotic factor in experimental heart transplantation. To address the second question (contribution of fibrocytes) we generated conditional collagen-1 deficient mice and crossed these mice with specific Cre-deleter mice. This process was time consuming and resulted in sufficient numbers of well characterized mice only during the last year of the funding period. Nevertheless, we were able to perform the suggested key experiments with the cell-type specific knock-out mice and could also successfully deplete fibrocytes with anti-GR1 antibodies as proposed. With these experiments we could demonstrate that apart from resident mesenchymal fibroblasts also infiltrating cells of hematopoietic origin (fibrocytes) significantly contribute to allograft fibrosis. We plan to continue transplant research in our group on the basis of a DFG-Sachbeihilfe to address the question how basophils are recruited into the transplants and how they are activated locally. In addition, we envisage to use a fibrosis model with cyclosporin A that we could establish during the funding period. So far all experiments were performed in a model of chronic transplant rejection with antibody-mediated depletion of CD4+ T cells to prevent acute rejection. As CD4+ T cells are an alternative source of IL-4, it will be important to find out, whether basophils and basophil-derived IL-4 will still be essential if immunosuppression is performed with cyclosporine A.
Publications
- (2010) Basophils support the survival of plasma cells in mice. J Immunol. 185:7180-7185
Rodriguez Gomez M, Talke Y, Goebel N, Hermann F, Reich B, Mack M
(See online at https://doi.org/10.4049/jimmunol.1002319) - (2011) Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J Exp Med. 208:23-39
London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung S, Schwartz M
(See online at https://doi.org/10.1084/jem.20101202) - (2012) Ly6C(hi) monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37:1076-1090
Zigmond E, Varol C, Farache J, Elmaliah E, Satpathy AT, Friedlander G, Mack M, Shpigel N, Boneca IG, Murphy KM, Shakhar G, Halpern Z, Jung S
(See online at https://doi.org/10.1016/j.immuni.2012.08.026) - (2012) Monocytes control second-phase neutrophil emigration in established LPS-induced murine lung injury. Am J Respir Crit Care Med. 186:514-524
Dhaliwal K, Scholefield E, Ferenbach D, Gibbons M, Duffin R, Dorward DA, Morris AC, Humphries D, MacKinnon A, Wilkinson TS, Wallace WA, Rooijen N, Mack M, Rossi AG, Davidson DJ, Hirani N, Hughes J, Haslett C, Simpson A
(See online at https://doi.org/10.1164/rccm.201112-2132OC) - (2013) Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 84(1):78-89
Reich B, Schmidbauer K, Rodriguez Gomez M, Hermann F, Göbel N, Brühl H, Ketelsen I, Talke Y, Mack M
(See online at https://doi.org/10.1038/ki.2013.84) - (2013) Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 84:78-89
Reich B, Schmidbauer K, Rodriguez Gomez M, Johannes Hermann F, Gobel N, Bruhl H, Ketelsen I, Talke Y and Mack M
(See online at https://doi.org/10.1038/ki.2013.84) - (2013) Functional macrophage heterogeneity in a mouse model of autoimmune central nervous system pathology. J Immunol. 190:3570-3578
London A, Benhar I, Mattapallil MJ, Mack M, Caspi RR and Schwartz M
(See online at https://doi.org/10.4049/jimmunol.1202076) - (2013). Inhibition of innate co-receptor TREM-1 signaling reduces CD4+ T cell activation and prolongs cardiac allograft survival. Am J Transplant. 13:1168-1180
Schiechl G, Brunner SM, Kesselring R, Martin M, Ruemmele P, Mack M, Hirt SW, Schlitt HJ, Geissler EK, Fichtner-Feigl S
(See online at https://doi.org/10.1111/ajt.12186) - (2014) Basophil expansion protects against invasive pneumococcal disease in mice. J Infect Dis. 210:14-24
Bischof A, Brumshagen C, Ding N, Kirchhof G, Briles DE, Gessner JE, Welte T, Mack M and Maus UA
(See online at https://doi.org/10.1093/infdis/jiu056) - (2014) Basophils control T-cell responses and limit disease activity in experimental murine colitis. Mucosal Immunol. 7:188-199
Rodriguez Gomez M, Talke Y, Hofmann C, Ketelsen I, Hermann F, Reich B, Goebel N, Schmidbauer K, Dunger N, Bruhl H, Renner K, Syed SN and Mack M
(See online at https://doi.org/10.1038/mi.2013.38) - (2014) Basophils inhibit proliferation of CD4 T cells in autologous and allogeneic mixed lymphocyte reactions and limit disease activity in a murine model of graft versus host disease. Immunology 145(2):202-212
Hermann FJ, Rodriguez Gomez M, Doser K, Edinger M, Hoffmann P, Schiechl G, Talke Y, Gobel N, Schmidbauer K, Bruhl H and Mack M
(See online at https://doi.org/10.1111/imm.12436) - (2014) Resolution of acute inflammation bridges the gap between innate and adaptive immunity. Blood 124:1748-1764
Newson J, Stables M, Karra E, Arce-Vargas F, Quezada S, Motwani M, Mack M, Yona S, Audzevich T and Gilroy DW
(See online at https://doi.org/10.1182/blood-2014-03-562710) - (2015) Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int. 87:297-307
Mack M and Yanagita M
(See online at https://doi.org/10.1038/ki.2014.287) - (2016) Basophils trigger fibroblast activation in cardiac allograft fibrosis development. Am J Transplant. 16(9):2574-2588
Schiechl, G, Hermann, FJ, Rodriguez Gomez, M, Kutzi, S, Schmidbauer, K, Talke, Y, Neumayer, S, Goebel, N, Renner, K, Bruhl, H, Karasuyama, H, Obata-Ninomiya, K, Utpatel, K, Evert, M, Hirt, SW, Geissler, EK, Fichtner-Feigl, S and Mack, M
(See online at https://doi.org/10.1111/ajt.13764) - (2016) Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat Commun 2016. 7
Bain, CC, Hawley, CA, Garner, H, Scott, CL, Schridde, A, Steers, NJ, Mack, M, Joshi, A, Guilliams, M, Mowat, AM, Geissmann, F and Jenkins, SJ
(See online at https://doi.org/10.1038/ncomms11852) - (2017) Effects of reduced kidney function because of living kidney donation on left ventricular mass. Hypertension 2017. 69: 297-303
Altmann, U, Boger, CA, Farkas, S, Mack, M, Luchner, A, Hamer, OW, Zeman, F, Debl, K, Fellner, C, Jungbauer, C, Banas, B and Buchner, S
(See online at https://doi.org/10.1161/hypertensionaha.116.08175)
