title: Cytokine Release After Treatment With Rituximab in Renal Transplant Recipients.
abstract: BACKGROUND
  Treatment with rituximab may be accompanied by a systemic cytokine release. We studied the effects of a single dose of rituximab on cytokine levels in transplant patients and examined the underlying mechanism.
  
  
  METHODS
  Twenty renal transplant recipients (10 rituximab-treated, 10 placebo-treated) were recruited from a randomized clinical trial. Rituximab or placebo was infused during surgery, and blood samples were taken before, during, and after surgery and analyzed for interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, IL-17, interferon-γ, macrophage inflammatory protein (MIP)-1β, transforming growth factor-β, and tumor necrosis factor-α. in vitro, healthy donor peripheral blood mononuclear cells, purified B cells, monocytes, natural killer (NK) cells, or combinations thereof were incubated with rituximab, rituximab-F(ab')2, or medium and MIP-1β, IL-10, interferon-γ, and tumor necrosis factor-α levels were measured in the supernatant.
  
  
  RESULTS
  Rituximab-treated patients had higher serum levels of IL-10 (101 ± 35 pg/mL vs 41 ± 9 pg/mL; P < 0.01) and MIP-1β (950 ± 418 pg/mL vs 125 ± 32 pg/mL; P < 0.001) compared to placebo-treated patients at 2 hours after start of infusion. There was no difference in the level of other cytokines. In vitro, the addition of rituximab, but not rituximab-F(ab')2 fragments, only led to significantly increased levels of MIP-1β in co-cultures of B and NK cells. Levels of MIP-1β were higher in patients with a high affinity Fc-receptor compared to those with a lower affinity FcγRIIIa (1356 ± 184 pg/mL vs 679 ± 273 pg/mL; P < 0.01).
  
  
  CONCLUSIONS
  In addition to B-cell depletion, rituximab can modulate the immune response by inducing cytokine secretion, especially IL-10 and MIP-1β. Rituximab-induced MIP-1β secretion depends on the combined presence of B cells and FcR-bearing cells, especially NK cells.
authors: 1 Department of Laboratory Medicine-Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands. 2 Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Elena G
authors: EG
authors: Kamburova
authors: Martijn W F
authors: MW
authors: van den Hoogen
authors: Hans J P M
authors: HJ
authors: Koenen
authors: Marije C
authors: MC
authors: Baas
authors: Luuk B
authors: LB
authors: Hilbrands
authors: Irma
authors: I
authors: Joosten
mesh_terms: D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000097:blood; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood*; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood; D016030:Kidney Transplantation / Q000009:adverse effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015415:Biomarkers; C066507:CCL4 protein, human; D054407:Chemokine CCL4; D016207:Cytokines; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D016753:Interleukin-10; D000069283:Rituximab