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• W2005698810 abstract "IntroductionAllogeneic hematopoietic cell transplantation (HCT) offers a unique opportunity to monitor the development of immune reconstitution using the patient as his or her own control. Furthermore, the donor serves as an HLA-identical normal control and source of adoptive immune transfer. Donor hematopoietic stem cells (HSCs) differentiate and proliferate to repopulate all blood lineages providing normal cell numbers of red blood cells, platelets, and neutrophils. Successful immune reconstitution and protection from infection requires antimicrobial B cell and antibody development. Studies of B cell reconstitution after HCT have primarily examined immunoglobulin concentration, B cell quantification, and antimicrobial antibody development in relation to donor/recipient serologic status or vaccination.Following HCT, humoral immunity has 3 distinct contributions. First, recipient antibody persists with an average half-life of 30-60 days, and some recipient plasma cells persist for years following allogeneic HCT [1van Tol M.J. Gerritsen E.J. de Lange G.G. et al.The origin of IgG production and homogeneous IgG components after allogeneic bone marrow transplantation.Blood. 1996; 87: 818-826PubMed Google Scholar] providing protective antimicrobial humoral immunity [2Wimperis J.Z. Brenner M.K. Prentice H.G. Thompson E.J. Hoffbrand A.V. B cell development and regulation after T cell-depleted marrow transplantation.J Immunol. 1987; 138: 2445-2450PubMed Google Scholar]. Some recipient antidonor alloimmune responses are detrimental contributring to primary graft rejection [3Petersdorf E.W. Hansen J.A. Martin P.J. et al.Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.N Engl J Med. 2001; 345: 1794-1800Crossref PubMed Scopus (270) Google Scholar, 4Taylor P.A. Ehrhardt M.J. Roforth M.M. et al.Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients.Blood. 2007; 109: 1307-1315Crossref PubMed Scopus (90) Google Scholar] and prolonged red cell aplasia when donors and recipients are ABO major mismatched [5Bolan C.D. Leitman S.F. Griffith L.M. et al.Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation.Blood. 2001; 98: 1687-1694Crossref PubMed Scopus (156) Google Scholar, 6Griffith L.M. McCoy Jr., J.P. Bolan C.D. et al.Persistence of recipient plasma cells and anti-donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non-myeloablative haematopoietic cell transplantation.Br J Haematol. 2005; 128: 668-675Crossref PubMed Scopus (92) Google Scholar]. Second, donor grafts contain naïve and memory B cells that have already undergone positive and negative selection in the HLA-identical donor and contribute adoptive antimicrobial and alloreactive B cells. Third, B cells reconstituting from donor HSCs recognizing disparate recipient antigens as “self” will be clonally deleted, preventing alloreactive responses, but remain capable of responding to infectious challenges and vaccinations. This educational session will consider B cell responses following allogeneic HCT as they contribute to (1) vaccine-induced antimicrobial immunity, (2) autoimmune responses, and (3) allogeneic antibody responses. We will discuss a B cell role in chronic graft-versus-host diease (cGVHD) pathogenesis, review anti-B cell cGVHD therapy using rituximab, and, finally, consider the pathogenic role of agonistic antibodies targeting platelet-derived growth factor receptor (PDGFR).Normal B Cell OntogenyB cell development is schematically depicted in Figure 1. Progenitor B cells receive signals from essential bone marrow stromal cells via cell-cell contacts and secreted signals. Stem cell factor (SCF) on stromal cell membranes binds ckit (CD117) on the lymphocyte membrane, and secreted cytokines, especially interleukin (IL)-7, promote B cell development [7Brown V.I. Hulitt J. Fish J. et al.Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling.Cancer Res. 2007; 67: 9963-9970Crossref PubMed Scopus (55) Google Scholar, 8Dai X. Chen Y. Di L. et al.Stat5 is essential for early B cell development but not for B cell maturation and function.J Immunol. 2007; 179: 1068-1079PubMed Google Scholar, 9Kalis S.L. Zhai S.K. Yam P.C. Witte P.L. Knight K.L. Suppression of B lymphopoiesis at a lymphoid progenitor stage in adult rabbits.Int Immunol. 2007; 19: 801-811Crossref PubMed Scopus (14) Google Scholar]. B cells bind antigen with varying affinity through B cell receptors that gain diversity through intrachromosomal variable (V) and constant (C) region recombination [10Koralov S.B. Muljo S.A. Galler G.R. et al.Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage.Cell. 2008; 132: 860-874Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar]. B cell positive selection requires tonic signaling through membrane pre-B receptor and membrane IgM expression for the B cell to survive. Mouse knock-out experiments expressing null alleles of the heavy chain transmembrane exon, Iga or Igb genes, or their ITAMs prevents B cell development [11Meffre E. Nussenzweig M.C. Deletion of immunoglobulin beta in developing B cells leads to cell death.Proc Natl Acad Sci USA. 2002; 99: 11334-11339Crossref PubMed Scopus (43) Google Scholar, 12Pfeifhofer C. Gruber T. Letschka T. et al.Defective IgG2a/2b class switching in PKC alpha−/− mice.J Immunol. 2006; 176: 6004-6011PubMed Google Scholar]. Likewise, productive somatic recombination leads to allelic exclusion for both heavy and light chains in each individual B cell. B cells recognizing self antigens are negatively selected before emerging from the bone marrow.Accumulating data suggests the BCR affinity “threshold” is influenced by cytokine tumor necrosis factor (TNF) family member B cell-activating factor (BAFF; also termed BLyS). Three receptors have been identified that bind to BAFF: transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); B cell maturation Ag (BCMA); and BAFF-R. Baff-R(−/−) mice mount significant, but reduced, Ag-specific Ab responses [13Sasaki Y. Casola S. Kutok J.L. Rajewsky K. Schmidt-Supprian M. TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology.J Immunol. 2004; 173: 2245-2252PubMed Google Scholar]. BAFF and its receptors, play a crucial role in peripheral B cell selection and survival, by dictating the set point for the number of mature primary B cells and adjusting thresholds for specificity-based selection during transitional differentiation [14Calame K.L. Mechanisms that regulate immunoglobulin gene expression.Annu Rev Immunol. 1985; 3: 159-195Crossref PubMed Scopus (60) Google Scholar, 15Calame K.L. Lin K.I. Tunyaplin C. Regulatory mechanisms that determine the development and function of plasma cells.Annu Rev Immunol. 2003; 21: 205-230Crossref PubMed Scopus (290) Google Scholar]. Transgenic models demonstrate that antigen-induced anergy and exclusion from follicular niches of autoreactive B cells depends on the presence or absence of a diverse B cell pool [16Cyster J.G. Hartley S.B. Goodnow C.C. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire.Nature. 1994; 371: 389-395Crossref PubMed Scopus (473) Google Scholar]. In addition, B cell reconstitution and homeostasis after myeloablation requires the B survival factor BAFF [17Gorelik L. Gilbride K. Dobles M. Kalled S.L. Zandman D. Scott M.L. Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells.J Exp Med. 2003; 198: 937-945Crossref PubMed Scopus (208) Google Scholar]. Limiting amounts of BAFF are required for ongoing B cell turnover and avoidance of B cell autoreactivity [18Miller J.P. Stadanlick J.E. Cancro M.P. Space, selection, and surveillance: setting boundaries with BLyS.J Immunol. 2006; 176: 6405-6410PubMed Google Scholar]. This is because in the setting of a limited B cell pool, excess BAFF promotes the survival of autoreactive B cells [19Thien M. Phan T.G. Gardam S. et al.Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches.Immunity. 2004; 20: 785-798Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar]. These BAFF homeostatic demands suggest a paradigm that unites peripheral negative and positive selection with the maintenance of mature B cell numbers [20Cancro M.P. Living in context with the survival factor BAFF.Immunity. 2008; 28: 300-301Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 21De Falco M. Oliva G. Ragusa M. et al.Surgical treatment of differentiated thyroid carcinoma: a retrospective study.G Chir. 2008; 29: 152-158PubMed Google Scholar] that probably have an impact on post-HCT reconstitution. Plasma BAFF levels are markedly elevated following myeloablative conditioning and decrease as lymphocyte numbers recover. Elevated BAFF has been associated with cGVHD [22Sarantopoulos S. Stevenson K.E. Kim H.T. et al.High levels of B-cell activating factor in patients with active chronic graft-versus-host disease.Clin Cancer Res. 2007; 13: 6107-6114Crossref PubMed Scopus (193) Google Scholar] and autoimmune diseases [23Gross J.A. Johnston J. Mudri S. et al.TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.Nature. 2000; 404: 995-999Crossref PubMed Scopus (988) Google Scholar, 24Mackay F. Browning J.L. BAFF: a fundamental survival factor for B cells.Nat Rev Immunol. 2002; 2: 465-475Crossref PubMed Scopus (557) Google Scholar, 25Mariette X. Roux S. Zhang J. et al.The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren's syndrome.Ann Rheum Dis. 2003; 62: 168-171Crossref PubMed Scopus (457) Google Scholar].Antibody Reconstitution after HCTEarly studies showed IgG and IgM return to normal concentrations 3-4 months after allogeneic HCT [26Halterman R.H. Graw Jr., R.G. Fuccillo D.A. Leventhal B.G. Immunocompetence following allogeneic bone marrow transplantation in man.Transplantation. 1972; 14: 689-697Crossref PubMed Scopus (21) Google Scholar, 27Fass L. Ochs H.D. Thomas E.D. Mickelson E. Storb R. Fefer A. Studies of immunological reactivity following syngeneic or allogeneic marrow grafts in man.Transplantation. 1973; 16: 630-640Crossref PubMed Scopus (61) Google Scholar], whereas B cells are quantitatively deficient during the first month and persists in some patients for more than a year after allo-HCT [28Asma G.E. van den Bergh R.L. Vossen J.M. Regeneration of TdT+, pre-B, and B cells in bone marrow after allogeneic bone marrow transplantation.Transplantation. 1987; 43: 865-870Crossref PubMed Scopus (20) Google Scholar, 29Small T.N. Keever C.A. Weiner-Fedus S. Heller G. O'Reilly R.J. Flomenberg N. B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny.Blood. 1990; 76: 1647-1656PubMed Google Scholar, 30Leitenberg D. Rappeport J.M. Smith B.R. B-cell precursor bone marrow reconstitution after bone marrow transplantation.Am J Clin Pathol. 1994; 102: 231-236PubMed Google Scholar]. Antibody assessment is complicated by blood product support transferring significant immunoglobulin and antibody half-life extending 30-60 days. Nonetheless, vaccination with neoantigens phage φX174 and keyhole limpet hemocyanin (KLH) demonstrated effective IgG responses 6 months after HCT, but antibody response lagged in patients with cGVHD or those who received antithymocyte globulin (ATG) [31Witherspoon R.P. Storb R. Ochs H.D. et al.Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment.Blood. 1981; 58: 360-368PubMed Google Scholar]. A reduced immunoglobulin repertoire persists for at least 2 years after HCT with oligoclonal dominance [32Gerritsen E.J. van Tol M.J. Lankester A.C. et al.Immunoglobulin levels and monoclonal gammopathies in children after bone marrow transplantation.Blood. 1993; 82: 3493-3502PubMed Google Scholar, 33Mitus A.J. Stein R. Rappeport J.M. et al.Monoclonal and oligoclonal gammopathy after bone marrow transplantation.Blood. 1989; 74: 2764-2768PubMed Google Scholar]. The diversity of heavy IgG VDJ gene rearrangement reflects a broad adult μ-chain useage arguing against a recapitulation of fetal ontogeny [34Raaphorst F.M. Reconstitution of the B cell repertoire after bone marrow transplantation does not recapitulate human fetal development.Bone Marrow Transplant. 1999; 24: 1267-1272Crossref PubMed Scopus (23) Google Scholar]. Post-HCT IgH repertoire is characterized by decreased somatic hypermutation [35Suzuki I. Milner E.C. Glas A.M. et al.Immunoglobulin heavy chain variable region gene usage in bone marrow transplant recipients: lack of somatic mutation indicates a maturational arrest.Blood. 1996; 87: 1873-1880PubMed Google Scholar], delayed class-switching [36Gokmen E. Raaphorst F.M. Boldt D.H. Teale J.M. Ig heavy chain third complementarity determining regions (H CDR3s) after stem cell transplantation do not resemble the developing human fetal H CDR3s in size distribution and Ig gene utilization.Blood. 1998; 92: 2802-2814Crossref PubMed Google Scholar], and oligoclonal dominance [37Nasman I. Lundkvist I. Evidence for oligoclonal diversification of the VH6-containing immunoglobulin repertoire during reconstitution after bone marrow transplantation.Blood. 1996; 87: 2795-2804PubMed Google Scholar, 38Nasman-Bjork I. Lundkvist I. Oligoclonal dominance of immunoglobulin VH3 rearrangements following allogeneic bone marrow transplantation.Bone Marrow Transplant. 1998; 21: 1223-1230Crossref PubMed Scopus (17) Google Scholar].Analysis of herpes simplex virus (HSV) and cytomegalovirus (CMV) clarified that antiviral Ab responses were of recipient origin for the first year post-HCT [2Wimperis J.Z. Brenner M.K. Prentice H.G. Thompson E.J. Hoffbrand A.V. B cell development and regulation after T cell-depleted marrow transplantation.J Immunol. 1987; 138: 2445-2450PubMed Google Scholar, 39Wimperis J.Z. Berry N.J. Brenner M.K. et al.Production of anti-cytomegalovirus antibody following T-cell depleted bone marrow transplant.Br J Haematol. 1986; 63: 659-664Crossref PubMed Scopus (8) Google Scholar, 40Brenner M.K. Wimperis J.Z. Reittie J.E. et al.Recovery of immunoglobulin isotypes following T-cell depleted allogeneic bone marrow transplantation.Br J Haematol. 1986; 64: 125-132Crossref PubMed Scopus (27) Google Scholar]. Persistent high-titer IgG responses persisted when recipients were seropositive and donors seronegative, and likewise recipients remained seronegative even when the donor was seropositive unless viral infection erupted [41Wimperis J.Z. Berry N.J. Prentice H.G. Lever A. Griffiths P.D. Brenner M.K. Regeneration of humoral immunity to herpes simplex virus following T-cell-depleted allogeneic bone marrow transplantation.J Med Virol. 1987; 23: 93-99Crossref PubMed Scopus (5) Google Scholar]. Deliberate vaccination of donors pretransplant with a protein recall antigen, such as tetanus toxoid [42Wimperis J.Z. Brenner M.K. Prentice H.G. et al.Transfer of a functioning humoral immune system in transplantation of T-lymphocyte-depleted bone marrow.Lancet. 1986; 1: 339-343Abstract PubMed Scopus (123) Google Scholar], or neoantigen KLH [43Wimperis J.Z. Gottlieb D. Duncombe A.S. Heslop H.E. Prentice H.G. Brenner M.K. Requirements for the adoptive transfer of antibody responses to a priming antigen in man.J Immunol. 1990; 144: 541-547PubMed Google Scholar], could demonstrate adoptive B cell transfer but antibody development still required recipient revaccination after transplant.Donor and Recipient Antibody Contribution Can Be Distinguished by AllotypeAllotype-specific monoclonal antibodies (mAbs) specifically bind single amino acid polymorphisms located in the immunoglobulin constant fragment of specific IgG isotypes [44Steinberg A.G. Cook C.E. The Distribution of Human Immunoglobin Allotype. Oxford university Press, Oxford1981Google Scholar]. If either the donor or recipient is homozygous null for an allotype then the HCT pair is informative allowing antibody origin to be determined. For example, if the recipient is null for IgG1 detection using allotype reagent, then the development of donor derived IgG1 is allotype detected. Such allotype reagents provided the first evidence of donor B cell reconstitution after HCT [45Witherspoon R.P. Schanfield M.S. Storb R. Thomas E.D. Giblett E.R. Immunoglobulin production of donor origin after marrow transplantation for acute leukemia or aplastic anemia.Transplantation. 1978; 26: 407-408Crossref PubMed Scopus (64) Google Scholar], and that some recipient plasma cells persist for years after myeloablative HCT. In a pediatric study, 8 of 13 informative pairs showed some persistent recipient IgG more than a year and some 8 years after myeloablative allogeneic HCT [1van Tol M.J. Gerritsen E.J. de Lange G.G. et al.The origin of IgG production and homogeneous IgG components after allogeneic bone marrow transplantation.Blood. 1996; 87: 818-826PubMed Google Scholar]. More recently, IgG allotype studies showed recipient antimicrobial IgG predominates following reduced-intensity conditioning (RIC) HCT, and DNA chimerism confirmed that the majority of bone marrow plasma cells remained recipient derived 1 year after RIC allo-HCT [46Boiko J, Sahaf B, Mueller A, Chen G, Tyan D, Miklos D. IgG allotypes identify long-lived recipient plasma-cell responses after reduced-intensity hematopoietic cell transplantation. Abstract #349. American Society of Hematology 2008 Meeting. San Francisco, CA.Google Scholar]. In support of this recipient humoral immunity predominance, a study of 87 patients randomized to receive either marrow or peripheral blood stem cells (PBSCs) showed vaccine-specific antibody responses in the first year after allo-HCT reflected primarily the recipient's pretransplant titer [47Storek J. Viganego F. Dawson M.A. et al.Factors affecting antibody levels after allogeneic hematopoietic cell transplantation.Blood. 2003; 101: 3319-3324Crossref PubMed Scopus (49) Google Scholar]. Thus, humoral immunity is predominately recipient derived for the first year after RIC allogeneic HCT, and this persistent recipient derived antimicrobial IgG may benefit RIC allo-HCT patient and contribute to their decreased treatment related mortality (TRM).Immunogenicity of Vaccines following HCTVaccine preventable infections, such as pneumococcus [48Chen C.S. Boeckh M. Seidel K. et al.Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation.Bone Marrow Transplant. 2003; 32: 515-522Crossref PubMed Scopus (83) Google Scholar], influenza [49Machado C.M. Cardoso M.R. da Rocha I.F. Boas L.S. Dulley F.L. Pannuti C.S. The benefit of influenza vaccination after bone marrow transplantation.Bone Marrow Transplant. 2005; 36: 897-900Crossref PubMed Scopus (97) Google Scholar], and varicella [50Koc Y. Miller K.B. Schenkein D.P. et al.Varicella zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors, and clinical outcome.Biol Blood Marrow Transplant. 2000; 6: 44-49Abstract Full Text PDF PubMed Scopus (186) Google Scholar] remain a significant cause of morbidity, rehospitalization, and mortality after successful HCT. Despite the fact that influenza infections remain a significant cause of serious upper and lower respiratory tract infections post-HCT, many patients do not receive their yearly influenza immunization. Most studies report a 30% to 40% incidence of reactivation of varicella zoster virus (VZV) following HCT. In a retrospective study of 100 consecutive allogeneic HCT recipients, 41% developed a VZV infection at a median of 227 (range: 45–346) days posttransplantation [50Koc Y. Miller K.B. Schenkein D.P. et al.Varicella zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors, and clinical outcome.Biol Blood Marrow Transplant. 2000; 6: 44-49Abstract Full Text PDF PubMed Scopus (186) Google Scholar]. Forty percent of patients required admission to the hospital, with a mean stay of 7.2 days. Postherpetic neuralgia and peripheral neuropathy developed in 68% of patients [18Miller J.P. Stadanlick J.E. Cancro M.P. Space, selection, and surveillance: setting boundaries with BLyS.J Immunol. 2006; 176: 6405-6410PubMed Google Scholar]. As such, revaccinating HCT patients prevents significant morbidity and mortality, and, in addition, well-designed vaccine studies functionally assess B cell immune reconstitution.Protective Immunity Dissipates after Myeloablative HCTMultiple studies have demonstrated that in the absence of revaccination, both autologous and allogeneic transplant recipients lose seroprotection to pathogens they were immunized against during childhood (reviewed in [51Ljungman P. Engelhard D. de la Camara R. et al.Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT.Bone Marrow Transplant. 2005; 35: 737-746Crossref PubMed Scopus (191) Google Scholar, 52Machado C.M. Reimmunization after hematopoietic stem cell transplantation.Expert Rev Vaccines. 2005; 4: 219-228Crossref PubMed Scopus (20) Google Scholar]). Although there is some variability in the time to protective titer loss among different transplant groups, loss of pneumococcal, H flu, and tetanus titers usually occur by 2 years post-HCT [53Parkkali T. Ruutu T. Stenvik M. et al.Loss of protective immunity to polio, diphtheria and Haemophilus influenzae type b after allogeneic bone marrow transplantation.APMIS. 1996; 104: 383-388Crossref PubMed Scopus (54) Google Scholar]. Residual titers against measles, mumps, and rubella persist longer after HCT [54Ljungman P. Aschan J. Barkholt L. et al.Measles immunity after allogeneic stem cell transplantation; influence of donor type, graft type, intensity of conditioning, and graft-versus host disease.Bone Marrow Transplant. 2004; 34: 589-593Crossref PubMed Scopus (36) Google Scholar]. These vaccine studies showing the loss of humoral immunity studied myeloablative HCT patients, therefore, RIC studies are needed.Vaccine LessonsRepetitive vaccination improves efficacyFollowing an HLA matched related bone marrow transplant (BMT), Ljungman et al. [55Ljungman P. Duraj V. Magnius L. Response to immunization against polio after allogeneic marrow transplantation.Bone Marrow Transplant. 1991; 7: 89-93PubMed Google Scholar] showed that 42%, 36%, and 21% of patients immunized with 1 inactivated polio virus vaccine (IPV) developed a 4-fold rise in titer against serotypes 1, 2, and 3, respectively. Following 3 doses, 50% of patients responded to all 3 serotypes. In contrast, Parkkali et al. [53Parkkali T. Ruutu T. Stenvik M. et al.Loss of protective immunity to polio, diphtheria and Haemophilus influenzae type b after allogeneic bone marrow transplantation.APMIS. 1996; 104: 383-388Crossref PubMed Scopus (54) Google Scholar] reported a 100% rate following 3 IPV whether administered at 6, 8, and 14 months (n = 23) or at 18, 20, and 26 months (n = 22). At Memorial Sloan Kettering Cancer Center (MSKCC), 96% of 219 allogeneic HCT recipients responded to a series of 3 IPV when administered following acquisition of minimal milestones of immune competence (CD4 >200/μL, PHA within 10% of normal, IgG >500 mg/dL) [56Jaffe D. Papadopoulos E.B. Young J.W. et al.Immunogenicity of recombinant hepatitis B vaccine (rHBV) in recipients of unrelated or related allogeneic hematopoietic cell (HC) transplants.Blood. 2006; 108: 2470-2475Crossref PubMed Scopus (56) Google Scholar]. There was no difference in response in related or unrelated HCT recipients, or those who received a T cell-depleted or T cell-replete HCT. The range of responses in these 3 studies may reflect in part variable levels of immune competence at the time of revaccination.Vaccine efficacy varies by glycosylation and conjugationAlthough most transplant patients respond well to vaccines containing bacterial toxoids, response to pure polysaccharide vaccines has been poor [57CDC CDC. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation.MMWR Morb Mortal Wkly Rep. 2000; 49: 1-125PubMed Google Scholar, 58EBMT: Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT P Ljungman1, D Engelhard1, R de la Cmara1, H Einsele1, A Locasciulli1, R Martino1, P Ribaud1, K Ward1 and C Cordonnier1 for the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.Google Scholar, 59Barra A. Cordonnier C. Preziosi M.P. et al.Immunogenicity of Haemophilus influenzae type b conjugate vaccine in allogeneic bone marrow recipients.J Infect Dis. 1992; 166: 1021-1028Crossref PubMed Scopus (79) Google Scholar, 60Guinan E.C. Molrine D.C. Antin J.H. et al.Polysaccharide conjugate vaccine responses in bone marrow transplant patients.Transplantation. 1994; 57: 677-684Crossref PubMed Scopus (123) Google Scholar]. Barra et al. [57CDC CDC. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation.MMWR Morb Mortal Wkly Rep. 2000; 49: 1-125PubMed Google Scholar] demonstrated that only 4 of 20 (25%) adult allogeneic transplant recipients immunized with a single nonconjugated H flu vaccine developed a specific IgG response compared to 11 of 20 patients recipients 1 H flu conjugate vaccine (Hib) (P < .05). Most studies have also shown that <25% of HCT recipients are capable of responding to the polyvalent polysaccharide vaccine, PPV23 [57CDC CDC. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation.MMWR Morb Mortal Wkly Rep. 2000; 49: 1-125PubMed Google Scholar, 58EBMT: Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT P Ljungman1, D Engelhard1, R de la Cmara1, H Einsele1, A Locasciulli1, R Martino1, P Ribaud1, K Ward1 and C Cordonnier1 for the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.Google Scholar, 59Barra A. Cordonnier C. Preziosi M.P. et al.Immunogenicity of Haemophilus influenzae type b conjugate vaccine in allogeneic bone marrow recipients.J Infect Dis. 1992; 166: 1021-1028Crossref PubMed Scopus (79) Google Scholar], as well as no benefit of donor vaccination with PPV23 prior to stem cell donation [60Guinan E.C. Molrine D.C. Antin J.H. et al.Polysaccharide conjugate vaccine responses in bone marrow transplant patients.Transplantation. 1994; 57: 677-684Crossref PubMed Scopus (123) Google Scholar]. Limited response to polysaccharide antigens post-HCT may be because of the predominance of immature B cells expressing CD1c, CD5, CD38, CD23+, B cells similar to the circulating B cells detected in cord blood and young children [29Small T.N. Keever C.A. Weiner-Fedus S. Heller G. O'Reilly R.J. Flomenberg N. B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny.Blood. 1990; 76: 1647-1656PubMed Google Scholar]. Limited responses may also reflect deficits in CD27+ memory B cells, a subset that may take years to recover even in children following HCT [61Pao M. Papadopoulos E. Kernan N. Jakubowski A. Young J. Castro-Malaspina H. Immunogenicity of haemophilus influenza and pneumococcal vaccines in related and unrelated transplant recipients.Blood. 2006; 108: 178aGoogle Scholar]. Nonetheless, heavy-chain IgG sequence analysis of Hib-specific B cells collected after Hib revaccination 9 months after myeloablative allogeneic BMT showed unique patterns of hypermutation, suggesting 90 of 121 (74%) were derived from only 16 precursors, and 12 of these clones were identified in the donor [62Storek J. Dawson M.A. Lim L.C. et al.Efficacy of donor vaccination before hematopoietic cell transplantation and recipient vaccination both before and early after transplantation.Bone Marrow Transplant. 2004; 33: 337-346Crossref PubMed Scopus (52) Google Scholar]. Thus, this single-patient study suggests memory B cells specific to Hib were transferred from the donor, persisted 9 months, and contributed the majority of Hib-specific repertoire.In contrast to the poor response to polysaccharide vaccines, response to protein-conjugated polysaccharide vaccines is significantly better, and can be enhanced by donor vaccination prior to the stem cell harvest [63Avanzini M.A. Locatelli F. Dos Santos C. et al.B lymphocyte reconstitution after hematopoietic stem cell transplantation: functional immaturity and slow recovery of memory CD27+ B cells.Exp Hematol. 2005; 33: 480-486Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 64Lausen B.F. Hougs L. Schejbel L. Heilmann C. Barington T. Human memory B cells transferred by allogenic bone marrow transplantation contribute significantly to the antibody repertoire of the recipient.J Immunol. 2004; 172:" @default.
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• W2005698810 title "B Cells and Transplantation: An Educational Resource" @default.
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