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B Cells and Transplantation: an Educational Resource B Cells and Transplantation: An Educational Resource Trudy N. Small,1 William H. Robinson,2 David B. Miklos2 INTRODUCTION neic HCT as they contribute to (1) vaccine-induced antimicrobial immunity, (2) autoimmune responses, Allogeneic hematopoietic cell transplantation (HCT) and (3) allogeneic antibody responses. We will discuss offers a unique opportunity to monitor the develop- a B cell role in chronic graft-versus-host diease ment of immune reconstitution using the patient as (cGVHD) pathogenesis, review anti-B cell cGVHD his or her own control. Furthermore, the donor therapy using rituximab, and, finally, consider the serves as an HLA-identical normal control and pathogenic role of agonistic antibodies targeting plate- source of adoptive immune transfer. Donor hemato- let-derived growth factor receptor (PDGFR). poietic stem cells (HSCs) differentiate and prolifer- ate to repopulate all blood lineages providing normal cell numbers of red blood cells, platelets, Normal B Cell Ontogeny and neutrophils. Successful immune reconstitution B cell development is schematically depicted in and protection from infection requires antimicrobial Figure 1. Progenitor B cells receive signals from essen- B cell and antibody development. Studies of B cell tial bone marrow stromal cells via cell-cell contacts and reconstitution after HCT have primarily examined secreted signals. Stem cell factor (SCF) on stromal cell immunoglobulin concentration, B cell quantification, membranes binds ckit (CD117) on the lymphocyte and antimicrobial antibody development in relation membrane, and secreted cytokines, especially interleu- to donor/recipient serologic status or vaccination. kin (IL)-7, promote B cell development [7-9]. B cells Following HCT, humoral immunity has 3 distinct bind antigen with varying affinity through B cell recep- contributions. First, recipient antibody persists with an tors that gain diversity through intrachromosomal var- average half-life of 30-60 days, and some recipient iable (V) and constant (C) region recombination [10].B plasma cells persist for years following allogeneic cell positive selection requires tonic signaling through HCT [1] providing protective antimicrobial humoral membrane pre-B receptor and membrane IgM expres- immunity [2]. Some recipient antidonor alloimmune sion for the B cell to survive. Mouse knock-out exper- responses are detrimental contributring to primary iments expressing null alleles of the heavy chain graft rejection [3,4] and prolonged red cell aplasia transmembrane exon, Iga or Igb genes, or their ITAMs when donors and recipients are ABO major mis- prevents B cell development [11,12]. Likewise, produc- matched [5,6]. Second, donor grafts contain naı¨ve tive somatic recombination leads to allelic exclusion for and memory B cells that have already undergone both heavy and light chains in each individual B cell. B positive and negative selection in the HLA-identical cells recognizing self antigens are negatively selected donor and contribute adoptive antimicrobial and allor- before emerging from the bone marrow. eactive B cells. Third, B cells reconstituting from do- Accumulating data suggests the BCR affinity nor HSCs recognizing disparate recipient antigens as ‘‘threshold’’ is influenced by cytokine tumor necrosis ‘‘self’’ will be clonally deleted, preventing alloreactive factor (TNF) family member B cell-activating factor responses, but remain capable of responding to infec- (BAFF; also termed BLyS). Three receptors have tious challenges and vaccinations. This educational been identified that bind to BAFF: transmembrane ac- session will consider B cell responses following alloge- tivator, calcium modulator, and cyclophilin ligand in- teractor (TACI); B cell maturation Ag (BCMA); and BAFF-R. Baff-R(2/2) mice mount significant, but re- From the 1Department of Pediatrics and Clinical Laboratory Med- duced, Ag-specific Ab responses [13]. BAFF and its re- icine, Memorial Sloan Kettering Cancer Center, New York, ceptors, play a crucial role in peripheral B cell selection New York; and 2Stanford University, Stanford, California. and survival, by dictating the set point for the number Financial disclosure: See Acknowledgments on page 110. of mature primary B cells and adjusting thresholds Correspondence and reprint requests: David B., Miklos, MD, PhD, for specificity-based selection during transitional dif- Stanford University, 450 Serra Mall, Stanford, CA 94305 (e-mail: [email protected]). ferentiation [14,15]. Transgenic models demonstrate 1083-8791/09/151S-0001$36.00/0 that antigen-induced anergy and exclusion from follic- doi:10.1016/j.bbmt.2008.10.016 ular niches of autoreactive B cells depends on the 104 Biol Blood Marrow Transplant 15:104-113, 2009 B Cells and Transplantation 105 IgM Antigen encounter Plasmablast IgD Plasma cell IgM CLP Progenitor Pre B cell Immature Transition Mature B B cell B cell B cell cell Plasma cell centroblast CD27 Memory B cell CD19 CD79a CD10 CD34 CD20 CD38 CD138 IgM and/or IgD Figure 1. B cell maturation profile. presence or absence of a diverse B cell pool [16]. In ad- were of recipient origin for the first year post-HCT dition, B cell reconstitution and homeostasis after [2,39,40]. Persistent high-titer IgG responses persisted myeloablation requires the B survival factor BAFF when recipients were seropositive and donors seroneg- [17]. Limiting amounts of BAFF are required for on- ative, and likewise recipients remained seronegative going B cell turnover and avoidance of B cell autoreac- even when the donor was seropositive unless viral tivity [18]. This is because in the setting of a limited B infection erupted [41]. Deliberate vaccination of donors cell pool, excess BAFF promotes the survival of autor- pretransplant with a protein recall antigen, such as eactive B cells [19]. These BAFF homeostatic demands tetanus toxoid [42], or neoantigen KLH [43], could suggest a paradigm that unites peripheral negative and demonstrate adoptive B cell transfer but antibody de- positive selection with the maintenance of mature B velopment still required recipient revaccination after cell numbers [20,21] that probably have an impact on transplant. post-HCT reconstitution. Plasma BAFF levels are markedly elevated following myeloablative condition- Donor and Recipient Antibody Contribution ing and decrease as lymphocyte numbers recover. Ele- Can Be Distinguished by Allotype vated BAFF has been associated with cGVHD [22] and Allotype-specific monoclonal antibodies (mAbs) autoimmune diseases [23-25]. specifically bind single amino acid polymorphisms located in the immunoglobulin constant fragment of Antibody Reconstitution after HCT specific IgG isotypes [44]. If either the donor or recip- Early studies showed IgG and IgM return to nor- ient is homozygous null for an allotype then the HCT mal concentrations 3-4 months after allogeneic HCT pair is informative allowing antibody origin to be deter- [26,27], whereas B cells are quantitatively deficient mined. For example, if the recipient is null for IgG1 during the first month and persists in some patients detection using allotype reagent, then the development for more than a year after allo-HCT [28-30]. Antibody of donor derived IgG1 is allotype detected. Such allo- assessment is complicated by blood product support type reagents provided the first evidence of donor B transferring significant immunoglobulin and antibody cell reconstitution after HCT [45], and that some re- half-life extending 30-60 days. Nonetheless, vaccina- cipient plasma cells persist for years after myeloablative tion with neoantigens phage 4X174 and keyhole lim- HCT. In a pediatric study, 8 of 13 informative pairs pet hemocyanin (KLH) demonstrated effective IgG showed some persistent recipient IgG more than responses 6 months after HCT, but antibody response a year and some 8 years after myeloablative allogeneic lagged in patients with cGVHD or those who received HCT [1]. More recently, IgG allotype studies showed antithymocyte globulin (ATG) [31]. A reduced immu- recipient antimicrobial IgG predominates following noglobulin repertoire persists for at least 2 years after reduced-intensity conditioning (RIC) HCT, and DNA HCT with oligoclonal dominance [32,33]. The diver- chimerism confirmed that the majority of bone marrow sity of heavy IgG VDJ gene rearrangement reflects a plasma cells remained recipient derived 1 year after broad adult m-chain useage arguing against a recapitula- RIC allo-HCT [46]. In support of this recipient hu- tion of fetal ontogeny [34]. Post-HCT IgH repertoire moral immunity predominance, a study of 87 patients is characterized by decreased somatic hypermutation randomized to receive either marrow or peripheral [35], delayed class-switching [36], and oligoclonal blood stem cells (PBSCs) showed vaccine-specific anti- dominance [37,38]. body responses in the first year after allo-HCT re- Analysis of herpes simplex virus (HSV) and cyto- flected primarily the recipient’s pretransplant titer megalovirus (CMV) clarified that antiviral Ab responses [47]. Thus, humoral immunity is predominately 106 T. N. Small et al. Biol Blood Marrow Transplant 15:104-113, 2009 recipient derived for the first year after RIC allogeneic months (n 5 22). At Memorial Sloan Kettering Cancer HCT, and this persistent recipient derived antimicro- Center (MSKCC), 96% of 219 allogeneic HCT recip- bial IgG may benefit RIC allo-HCT patient and con- ients responded to a series of 3 IPV when administered tribute to their decreased treatment related mortality following acquisition of minimal
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