The generation and maintenance of serum alloantibody

Abstract

Donor-specific alloantibodies (DSA) mediate hyperacute and acute antibody-mediated rejection (AMR), which can lead to early graft damage and loss, and are also associated with chronic AMR and reduced long-term graft survival. Such alloantibodies can be generated by previous exposure to major histocompatibility (MHC) antigens (usually via blood transfusions, previous allografts or pregnancy) or can occur de novo after transplantation. Recent studies also suggest that non-MHC antibodies, including those recognising major histocompatibility complex class I-related chain A (MICA), MICB, vimentin, angiotensin II type I receptor may also have an adverse impact on allograft outcomes. In this review, we consider how the dose, route and context of antigen exposure influences DSA induction and describe factors which control the generation, maintenance and survival of alloantibody-producing plasma cells. Finally, we discuss the implications of these variables on therapeutic approaches to DSA.

Figure 1

B cell activation and alloantibody production. (a) Alloantigen exposure occurs via pregnancy, blood transfusions and previous transplants. B cell activation occurs within secondary lymphoid organs (spleen and lymph nodes) and also possibly within tertiary lymphoid organs within allografts. The first step of B cell activation depends on the interaction between the B cell receptor (BCR) and its cognate antigen (A). Once activated, B cells migrate to the interface between the B follicle and the T-cell zone where they present antigen in the context of MHC class II molecules to cognate CD4+ T cells. Activated CD4 T cells provide help to B cells via co-stimulatory molecules such as CD40/CD40-L and by cytokine secretion. After T-dependent activation B cells can undergo two different fates; either they can migrate out of the B cell follicle and form extrafollicular plasmablasts responsible for the early production of low affinity antibody (b), or they enter the germinal centre where they undergo somatic hypermutation and class switch recombination (c). Mutated clones with higher affinity for antigen are positively selected and differentiate into memory B cells or plasma cells. (d) A small proportion of plasma cells arising from the germinal centre migrate to the bone marrow where they become long-lived plasma cells responsible for maintenance of antibody titres.

Figure 2

Factors affecting alloantibody production - Alloantibodies are produced by plasma cells. Alloantibody titres will therefore by determined by: (a) The provision of plasma cell survival factors by stromal cells within bone marrow niches, for example cytokines such as IL-6 and BAFF. (b) The rate of alloantibody production by plasma cells, which may be increased by TLR stimulation and blocked by CCL2. (c) The provision of additional, ectopic plasma cell niches within rejecting, inflamed allograft. (d) Factors affecting memory B cell activation.

Figure 3

Current (shown in black) and potential (shown in red) alloantibody-targeted therapies in transplantation. Current management strategies include: (a) antibody removal, using plasma exchange (PEX) or intravenous immunoglobulin (IVIG). (b) the prevention of DSA re-synthesis by depleting B cells using rituximab, depriving B cells of T cell help through T cell depletion using ATG, or depleting plasma cells with bortezomib. (c). Prevention of antibody mediated complement activation (eculizumab). Potential future therapeutic targets include blockade of survival factors for plasma cells and B cells, particularly those provided via BAFF or APRIL, blockade of T cell costimulation using belatacept or CD40L antagonist, or cross-linking of FcyRIIB on plasma cells to induce apoptosis.