A 65-year-old woman is enrolled in a clinical trial to test a new medication for rheumatoid arthritis. The patient's condition has been poorly controlled despite prolonged treatment with multiple disease-modifying antirheumatic drugs. The new medication is a CTLA4-Ig fusion protein that prevents CD28 from binding to CD80/86 on antigen-presenting cells. A month after treatment begins, the patient reports a significant reduction in joint pain and stiffness. Laboratory results reveal reduced levels of C-reactive protein and IL-2. Which of the following is the most likely underlying cause of this patient's treatment response?

Question

A 65-year-old woman is enrolled in a clinical trial to test a new medication for rheumatoid arthritis.  The patient's condition has been poorly controlled despite prolonged treatment with multiple disease-modifying antirheumatic drugs.  The new medication is a CTLA4-Ig fusion protein that prevents CD28 from binding to CD80/86 on antigen-presenting cells.  A month after treatment begins, the patient reports a significant reduction in joint pain and stiffness.  Laboratory results reveal reduced levels of C-reactive protein and IL-2.  Which of the following is the most likely underlying cause of this patient's treatment response?

Quizplus · Accepted Answer

11ec160b_37a2_cc5c_9249_3f9585045b0d_MD0001_00 Abatacept, a disease-modifying antirheumatic drug, is a fusion of CTLA4 with the Fc portion of IgG (CTLA4-Ig). CTLA4 is a naturally occurring immune checkpoint receptor that is upregulated on the surface of active T cells. It acts as a brake for the adaptive immune response by preventing the conversion of antigen-specific naive T cells into effector T cells. The activation of cytotoxic T cells requires 2 stimulatory signals. First, the T cell must bind to a specific antigen on the class I major histocompatibility complex (MHC) of an antigen-presenting cell (APC); then, the bound T cell must be costimulated by an interaction between the T cell surface receptor CD28 and the APC cell surface ligand CD80/86. T cells that bind an antigen on an APC but are not costimulated undergo anergy, a form of peripheral immune tolerance marked by a lack of T-cell response to cytokine, ligand, or antigen stimulation (T-cell inactivation). Because CTLA4 binds to CD80/86 with greater affinity than CD28, administration of exogenous CTLA4 (eg, abatacept) reduces the availability of ligands necessary for T cell costimulation, which dramatically increases T cell anergy in areas of active inflammation. (Choice A) C3a and C5a are potent anaphylatoxins, proinflammatory proteins that degranulate phagocytes/mast cells, increase vascular permeability, and recruit leukocytes. Although these 2 complement components generate significant inflammation, the complement system is not affected by CTLA4 inhibition. (Choice B) T cell anergy also impairs T cell-mediated B cell activation, which reduces antibody and inflammatory cytokine production. However, immune complex clearance by the reticuloendothelial system is unaffected by exogenous CTLA4 administration. (Choice C) Developing cytotoxic T cells that interact with self-antigens are eliminated in the thymus through negative selection, a form of central tolerance. Although this helps prevent autoimmunity, central tolerance is not mediated by CTLA4. (Choice E) Sensitization refers to the production of an allergen-specific IgE, which is mediated by CD4 helper type 2 lymphocytes after exposure to a specific antigen. CTLA4 does not play a role. Educational objective: Abatacept, a disease-modifying antirheumatic drug, is a fusion of CTLA4 with the Fc portion of IgG. CTLA4 binds to CD80/86 on antigen-presenting cells, which prevents CD80/86 from binding to CD28 on T cells. This reduces T cell costimulation and leads to anergy, which reduces inflammation.

A 65-Year-Old Woman Is Enrolled in a Clinical Trial to Test