INTRODUCTION: Macaque species offer a valuable model for translational allo-transplantation and tolerance studies. Cardiac allograft vasculopathy in Macaca fascicularis is associated with elaboration of anti-donor antibodies. Since T-independent pathways of B cell activation have been described, and anti-B cell strategies have proven to be a fruitful tolerogenic adjunct in rodent and xenogenic models, here we investigate whether an anti-CD20 antibody (rituximab) would be useful to deplete B-cells in a pre-clinical allo-transplantation setting in macaques. METHODS: Three cynomolgus macaques which had previously rejected a cardiac allograft and one with concurrent subacute vascular rejection were treated weekly with rituximab 20 mg/kg i.v. for 4 and 2 weeks, respectively. B-cell levels (CD19+ cells) were measured by flow cytometry in peripheral blood, spleen, lymph node and bone marrow cells at various intervals after initiation of treatment. B-cells and plasma cells were also analyzed by immunohistochemistry at necropsy in spleen, lymph node, tonsil and thymus tissue sections. Anti-donor antibody titers were measured by flow cytometry. RESULTS: B-cells expressing CD19 were not detectable in the peripheral blood in any animal within 24 h after initial treatment, or over the ensuing month. At necropsy, the germinal centers in spleen and lymph node were completely depleted of CD20+ B-cells in 2 animals, leaving a hypocellular trabecular pattern around preserved plasma cell follicles. Substantial but incomplete depletion of B-cells was demonstrated in the other 2 animals, in each instance immunohistochemical findings in spleen and lymph node exhibiting higher sensitivity for residual B-cells compared to FACS. Anti-donor antibody titers exhibited kinetics similar to untreated animals over this short follow-up. COMMENT: Treatment with anti-CD20 very efficiently depletes peripheral and tissue B-cells but not plasma cells in this macaque species. Biopsy of lymph node is necessary and may be sufficient to assess B-cell clearance in secondary lymphoid organs in this model.
INTRODUCTION: Macaque species offer a valuable model for translational allo-transplantation and tolerance studies. Cardiac allograft vasculopathy in Macaca fascicularis is associated with elaboration of anti-donor antibodies. Since T-independent pathways of B cell activation have been described, and anti-B cell strategies have proven to be a fruitful tolerogenic adjunct in rodent and xenogenic models, here we investigate whether an anti-CD20 antibody (rituximab) would be useful to deplete B-cells in a pre-clinical allo-transplantation setting in macaques. METHODS: Three cynomolgus macaques which had previously rejected a cardiac allograft and one with concurrent subacute vascular rejection were treated weekly with rituximab 20 mg/kg i.v. for 4 and 2 weeks, respectively. B-cell levels (CD19+ cells) were measured by flow cytometry in peripheral blood, spleen, lymph node and bone marrow cells at various intervals after initiation of treatment. B-cells and plasma cells were also analyzed by immunohistochemistry at necropsy in spleen, lymph node, tonsil and thymus tissue sections. Anti-donor antibody titers were measured by flow cytometry. RESULTS: B-cells expressing CD19 were not detectable in the peripheral blood in any animal within 24 h after initial treatment, or over the ensuing month. At necropsy, the germinal centers in spleen and lymph node were completely depleted of CD20+ B-cells in 2 animals, leaving a hypocellular trabecular pattern around preserved plasma cell follicles. Substantial but incomplete depletion of B-cells was demonstrated in the other 2 animals, in each instance immunohistochemical findings in spleen and lymph node exhibiting higher sensitivity for residual B-cells compared to FACS. Anti-donor antibody titers exhibited kinetics similar to untreated animals over this short follow-up. COMMENT: Treatment with anti-CD20 very efficiently depletes peripheral and tissue B-cells but not plasma cells in this macaque species. Biopsy of lymph node is necessary and may be sufficient to assess B-cell clearance in secondary lymphoid organs in this model.
Authors: Yulia Vugmeyster; Dhaya Seshasayee; Wesley Chang; Anahid Storn; Kathy Howell; Susan Sa; Tenea Nelson; Flavius Martin; Iqbal Grewal; Ellen Gilkerson; Ben Wu; Jeff Thompson; Barbara N Ehrenfels; Song Ren; An Song; Thomas R Gelzleichter; Dimitry M Danilenko Journal: Am J Pathol Date: 2006-02 Impact factor: 4.307
Authors: Antonio Fontanellas; Sandra Hervás-Stubbs; Itsaso Mauleón; Juan Dubrot; Uxua Mancheño; María Collantes; Ana Sampedro; Carmen Unzu; Carlos Alfaro; Asis Palazón; Cristian Smerdou; Alberto Benito; Jesús Prieto; Iván Peñuelas; Ignacio Melero Journal: Mol Ther Date: 2010-01-19 Impact factor: 11.454
Authors: Gadi Gazit Bornstein; Christophe Quéva; Mohammad Tabrizi; Anne van Abbema; Carlos Chavez; Ping Wang; Orit Foord; Kiran Ahluwalia; Naomi Laing; Sandhya Raja; Shenghua Wen; Larry L Green; Xiaodong Yang; Carl Webster; Ross Stewart; David Blakey Journal: Invest New Drugs Date: 2009-07-21 Impact factor: 3.850
Authors: Maria Rehnberg; Sylvie Amu; Andrej Tarkowski; Maria I Bokarewa; Mikael Brisslert Journal: Arthritis Res Ther Date: 2009-08-17 Impact factor: 5.156