It has been reported that B7H1 and B7H3 play a role in graft-versus-host disease (GVHD), the major cause of treatment-related mortality (TRM) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) patients; however, the prognostic value of these factors has not been defined. We retrospectively collected 64 haplo-HSCT patients in our hospital from 2013 to 2014, as well as 38 HLA-matched-HSCT patients during the same period as the control group. We analyzed B7H1, B7H3, PD1, soluble CD25, ST2 and TNFR1 at 0 day, + 7 days, + 14 days and + 28 days after HSCT. The + 7 days/+ 14 days B7H1/B7H3 and + 28 days ST2 serum levels were higher in patients with aGVHD who underwent haplo-HSCT. Moreover, + 7 days B7H1/B7H3 serum levels were predictive of grade III–IV aGVHD (B7H1: AUC = 0.830, P < 0.001; B7H3: AUC = 0.775, P = 0.001). Haplo-HSCT patients with higher + 7 days B7H1/B7H3 or + 28 days ST2 serum levels had poor GVHD-related mortality (GRM) (B7H1: P < 0.001; B7H3: P = 0.002; ST2: P = 0.047). Multivariate analysis revealed that the + 7 days B7H1 serum level (P = 0.041), as well as viral infection (P = 0.015) and donor age (P = 0.012), could independently predict GRM. Collectively, we found that + 7 days B7H1/B7H3 serum levels can predict grade III–IV aGVHD, while only the + 7 days B7H1 serum level, together with viral infection and donor age, could independently predict GRM in patients with haplo-HSCT.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Chang YJ, Luznik L, Fuchs EJ, Huang XJ. How do we choose the best donor for t-cell-replete, hla-haploidentical transplantation? J Hematol Oncol. 2016;9:35.
Meng L, Huang XJ. Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go. J Hematol Oncol. 2012;5:10.
Huang XJ. Current status of haploidentical stem cell transplantation for leukemia. J Hematol Oncol. 2008;1:27.
Juric MK, Shevtsov M, Mozes P, Ogonek J, Crossland RE, Dickinson AM, et al. B-cell-based and soluble biomarkers in body liquids for predicting acute/chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:660.
Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, et al. Blood and marrow transplant clinical trials network. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015;2:e21-9.
Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61.
Hartwell MJ, Özbek U, Holler E, Renteria AS, Major-Monfried H, Reddy P, et al. An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight. 2017;2:e89798.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M. at al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.
Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487–96.
Socie G, Ritz J, Martin PJ. Current challenges in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:146-51.
Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168–73.
Ali AM, DiPersio JF, Schroeder MA. A proposed biology-and biomarker-based algorithm for management of acute GvHD. Bone Marrow Transplant. 2016;52:337–40.
Renteria AS, Levine JE, Ferrara JL. Development of a biomarker scoring system for use in graft-versus-host disease. Biomark Med. 2016;10:793–5.
Paczesny S, Krijanovski OI, Braun TM, Choi SW, Clouthier SG, Kuick R, et al. A biomarker panel for acute graft-versus-host disease. Blood. 2009;113:273–8.
Paczesny S, Braun TM, Levine JE, Hogan J, Crawford J, Coffing B, et al. Elafin is a biomarker of graft-versus-host disease of the skin. Sci Transl Med. 2010;2:13ra2.
Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011;118:6702–8.
Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT, Antin JH, et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013;369:529–39.
Li J, Lee Y, Li Y, Jiang Y, Lu H, Zang W, et al. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8+ T cells. Immunity. 2018;48:773–786.
Nagamatsu T, Barrier BF, Schust DJ. The regulation of T-cell cytokine production by ICOS-B7H2 interactions at the human fetomaternal interface. Immunol Cell Biol. 2011;89:417–25.
Singh AK, Stock P, Akbari O. Role of PD-L1 and PD-L2 in allergic diseases and asthma. Allergy. 2011;66:155–16.
Deng R, Cassady K, Li X, Yao S, Zhang M, Racine J, et al. B7H1/CD80 interaction augments PD-1-dependent T Cell apoptosis and ameliorates graft-versus-host disease. J Immunol. 2015;194:560–74.
Brennan TV, Yang Y. PD-L1 serves as a double agent in separating GVL from GVHD. J Clin Investig. 2017;127:1627–30.
Saha A, O’Connor RS, Thangavelu G, Lovitch SB, Dandamudi DB, Wilson CB, et al. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Investig. 2016;126:2642–60.
Ni X, Song Q, Cassady K, Deng R, Jin H, Zhang M, et al. PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Investig. 2017;127:1960–77.
Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2001;2:269–74.
Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, et al. Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci USA. 2004;101:12640–5.
Saatian B, Yu XY, Lane AP, Doyle T, Casolaro V, Spannhake EW. Expression of genes for B7-H3 and other T cell ligands by nasal epithelial cells during differentiation and activation. Am J Physiol Lung Cell Mol Physiol. 2004;287:217–25.
Veenstra RG, Flynn R, Kreymborg K, McDonald-Hyman C, Saha A, Taylor PA, et al. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Blood. 2015;125:3335–46.
Lv M, Chang Y, Huang X. Everyone has a donor: contribution of the Chinese experience to global practice of haploidentical hematopoietic stem cell transplantation. Front Med. https://doi.org/10.1007/s11684-017-0595-7.
Lorentino F, Labopin M, Fleischhauer K, Ciceri F, Mueller CR, Ruggeri A, et al. The impact of HLA matching on outcomes of unmanipulated haploidentical HSCT is modulated by GVHD prophylaxis. Blood Adv. 2017;1:669–80.
Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.
Mccurdy SR, Fuchs EJ. Comparable outcomes for hematologic malignancies after HLA-haploidentical transplantation with posttransplantation cyclophosphamide and HLA-matched transplantation. Adv Hematol. 2015;2015:431923.
Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, et al. Comparison of outcomes of hematopoietic cell transplants from T-replete haploidentical donors using post-transplantation cyclophosphamide with10 of 10 HLA-A. -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors and HLA-identical sibling donors: a multivariable analysis including disease risk index. Biol Blood Marrow Transplant. 2015;22:125–33.
McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolaños-Meade J, Rosner GL, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015;125:3024–31.
Paczesny S. Biomarkers for post-transplantation outcomes. Blood. 2018;131:2193–204.
Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. Immunity. 2004;20:327–36.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.
Hu Y, Lv X, Wu Y, Xu J, Wang L, Chen W, et al. Expression of costimulatory molecule B7-H3 and its prognostic implications in human acute leukemia. Hematology. 2015;20:187–95.
Wang F, Wang G, Liu T, Yu G, Zhang G, Luan X. B7-H3 was highly expressed in human primary hepatocellular carcinoma and promoted tumor progression. Cancer Investig. 2014;32,262 – 71.
Asakura S, Hashimoto D, Takashima S, Sugiyama H, Maeda Y, Akashi K, et al. Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice. J Clin Investig. 2010;120:2370–8.
Flutter B, Edwards N, Fallah-Arani F, Henderson S, Chai JG, Sivakumaran S, et al. Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J Clin Investig. 2010;120:3855–68.
Steinberger P, Majdic O, Derdak SV, Pfistershammer K, Kirchberger S, Klauser C, et al. Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains. J Immunol. 2004;172:2352–9.
Steinberger P. B7-H3 ameliorates GVHD. Blood. 2015;125:3219–21.
Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L, et al. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine. 2011;56:231–8.
Zhang G, Hou J, Shi J, Yu G, Lu B, Zhang X. Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology. 2008;123:538–46.
This work was supported in part by grants from the Natural Science Foundation of Jiangsu Province (BL20171205), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the National Natural Science Foundation of China (81302046, 81670164, 81730003), Innovation Capability Development Project of Jiangsu Province (BM2015004), National Key R&D Program of China (2016YFC0902800, 2017YFA0104502).
Conflict of interest
The authors declare no competing financial or non-financial interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhou, B., Wang, T., Lei, L. et al. Prognostic values of increased B7 family proteins in haploidentical hematopoietic stem cell transplantation patients with aGVHD. Int J Hematol 109, 451–462 (2019). https://doi.org/10.1007/s12185-019-02605-1