Costimulation Blockade Alters Germinal Center Responses and Prevents Antibody‐Mediated Rejection

De novo donor‐specific antibody (DSA) after organ transplantation promotes antibody‐mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti‐CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti‐CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM+ B cells, bela‐ and 2C10R4‐added groups maintained a predominant population of IgM+ B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4+CD28+CD95+) as well as PD‐1hiCD4+ T cells were decreased in both bela‐added and 2C10R4‐added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC‐follicular helper T (Tfh) cells, and IL‐21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.

[1]  Michael Y. Gerner,et al.  CD4 T follicular helper cell dynamics during SIV infection. , 2012, The Journal of clinical investigation.

[2]  S. Knechtle,et al.  Enhanced De Novo Alloantibody and Antibody‐Mediated Injury in Rhesus Macaques , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  K. Reimann,et al.  A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  A. Loupy,et al.  The impact of donor-specific anti-HLA antibodies on late kidney allograft failure , 2012, Nature Reviews Nephrology.

[5]  H. Haggerty,et al.  Chronic administration of belatacept, a T-cell costimulatory signal blocker, in cynomolgus monkeys. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[6]  P. Nickerson,et al.  Evolution and Clinical Pathologic Correlations of De Novo Donor‐Specific HLA Antibody Post Kidney Transplant , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  P. Terasaki.  A personal perspective: 100-year history of the humoral theory of transplantation. , 2012, Transplantation.

[8]  J. Hong,et al.  Spatial Alterations between CD4+ T Follicular Helper, B, and CD8+ T Cells during Simian Immunodeficiency Virus Infection: T/B Cell Homeostasis, Activation, and Potential Mechanism for Viral Escape , 2012, The Journal of Immunology.

[9]  P. Terasaki,et al.  The state of therapy for removal of alloantibody producing plasma cells in transplantation. , 2012, Seminars in immunology.

[10]  J. Bradley,et al.  Germinal Center Alloantibody Responses Are Mediated Exclusively by Indirect-Pathway CD4 T Follicular Helper Cells , 2012, The Journal of Immunology.

[11]  L. Rostaing,et al.  Three‐Year Outcomes from BENEFIT, a Randomized, Active‐Controlled, Parallel‐Group Study in Adult Kidney Transplant Recipients , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[12]  M. Jenkins,et al.  Origins of CD4+ effector and central memory T cells , 2011, Nature Immunology.

[13]  S. Crotty,et al.  Follicular helper CD4 T cells (TFH). , 2011, Annual review of immunology.

[14]  I. Messaoudi,et al.  Cytomegalovirus Latency Promotes Cardiac Lymphoid Neogenesis and Accelerated Allograft Rejection in CMV Naïve Recipients , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  I. McInnes,et al.  Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells , 2010, The Journal of Immunology.

[16]  R. Pierson,et al.  Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. , 2010, The Journal of clinical investigation.

[17]  C. King,et al.  New insights into the differentiation and function of T follicular helper cells , 2009, Nature Reviews Immunology.

[18]  P. Halloran,et al.  De Novo Donor‐Specific Antibody at the Time of Kidney Transplant Biopsy Associates with Microvascular Pathology and Late Graft Failure , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[19]  J. Fechner,et al.  BAFF Is Increased in Renal Transplant Patients Following Treatment with Alemtuzumab , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[20]  M. Ban,et al.  IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). , 2009, The Journal of clinical investigation.

[21]  Linda Mark,et al.  Follicular helper T cells as cognate regulators of B cell immunity. , 2009, Current opinion in immunology.

[22]  C. Hunter,et al.  With a little help from their friends: interleukin-21, T cells, and B cells. , 2008, Immunity.

[23]  Hao Wang,et al.  Inhibition of Terminal Complement Components in Presensitized Transplant Recipients Prevents Antibody-Mediated Rejection Leading to Long-Term Graft Survival and Accommodation1 , 2007, The Journal of Immunology.

[24]  Philip J. R. Goulder,et al.  PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression , 2006, Nature.

[25]  P. Linsley,et al.  Rational Development of LEA29Y (belatacept), a High‐Affinity Variant of CTLA4‐Ig with Potent Immunosuppressive Properties , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  R. Colvin,et al.  Campath‐1H Induction Plus Rapamycin Monotherapy for Renal Transplantation: Results of a Pilot Study , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[27]  A. Aruffo,et al.  Anti-CD40 therapy extends renal allograft survival in rhesus macaques1 , 2002, Transplantation.

[28]  C. Thompson,et al.  CD28 is required for germinal center formation. , 1996, Journal of immunology.

[29]  J. Bluestone,et al.  CD28/B7 system of T cell costimulation. , 1996, Annual review of immunology.

[30]  L. Glimcher,et al.  Two levels of help for B cell alloantibody production , 1996, The Journal of experimental medicine.

[31]  H. Ochs,et al.  Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction. , 1994, Journal of immunology.

[32]  N. Yoshida,et al.  The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. , 1994, Immunity.

[33]  H. Ochs,et al.  B cell activation via CD40 is required for specific antibody production by antigen-stimulated human B cells , 1993, The Journal of experimental medicine.

[34]  P. Pereira,et al.  T Cell‐Dependent B Cell Activation , 1984, Immunological reviews.

[35]  Woodruff,et al.  Undermine FDA , 2014 .