Abstract
Graft failure (GF) remains an obstacle to survival after allogeneic hematopoietic stem cell transplantation. However, differentiating GF from delayed engraftment (DE) can be difficult. Host CD8+ lymphocytes have been reported to mediate graft rejection, but the impact of macrophages on DE or GF is yet to be clarified. Peri-engraftment bone marrow (BM) specimens of 32 adult patients with normal engraftment, DE or GF were retrospectively evaluated to identify the potential associations of CD163+ macrophage and CD8+ lymphocyte infiltration into BM. The macrophage or CD8+ lymphocyte number/total nucleated cell number was defined as the Mac ratio and CD8 ratio, respectively. Both DE and GF groups had significantly higher Mac ratios at day 14 than the normal group (P<0.0001), but no significant difference was observed between the DE and GF groups (P=1.000). The CD8 ratio at day 14 was significantly higher in the GF than in the normal group (P=0.005), whereas the CD8 ratios of the DE and normal groups were similar (P=0.07). A high Mac ratio at day 14 was associated with a risk of DE or subsequent GF. Patients with increased CD8 ratio at day 14 had a further risk of GF. The Mac ratio and the CD8 ratio appear to be well suited for predicting engraftment status.
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References
Chan KW, Grimley MS, Taylor C, Wall DA . Early identification and management of graft failure after unrelated cord blood transplantation. Bone Marrow Transplant 2008; 42: 35–41.
Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant 2013; 48: 537–543.
Ruggeri A, Labopin M, Sormani MP, Sanz G, Sanz J, Volt F et al. Engraftment kinetics and graft failure after single umbilical cord blood transplantation using a myeloablative conditioning regimen. Haematologica 2014; 99: 1509–1515.
Cluzeau T, Lambert J, Raus N, Dessaux K, Absi L, Delbos F et al. Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI. Bone Marrow Transplant 2016; 51: 687–691.
Eapen M, Klein JP, Sanz GF, Spellman S, Ruggeri A, Anasetti C et al. Effect of donor-recipient HLA matching at HLA A, B, C and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 2011; 12: 1214–1221.
Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia 2015; 29: 1754–1762.
Ruggeri A, Rocha V, Masson E, Labopin M, Cunha R, Absi L et al. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Societe Francophone d'Histocompatibilite et d'Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis. Haematologica 2013; 98: 1154–1160.
Takanashi M, Atsuta Y, Fujiwara K, Kodo H, Kai S, Sato H et al. The impact of anti-HLA antibodies on unrelated cord blood transplantations. Blood 2010; 116: 2839–2846.
Yoshihara S, Maruya E, Taniguchi K, Kaida K, Kato R, Inoue T et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplant 2012; 47: 508–515.
Yoshihara S, Taniguchi K, Ogawa H, Saji H . The role of HLA antibodies in allogeneic SCT: is the 'type-and-screen' strategy necessary not only for blood type but also for HLA? Bone Marrow Transplant 2012; 47: 1499–1506.
Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.
Narimatsu H, Watanabe M, Kohno A, Sugimoto K, Kuwatsuka Y, Uchida T et al. High incidence of graft failure in unrelated cord blood transplantation using a reduced-intensity preparative regimen consisting of fludarabine and melphalan. Bone Marrow Transplant 2008; 41: 753–756.
Slot S, Smits K, van de Donk NW, Witte BI, Raymakers R, Janssen JJ et al. Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis. Bone Marrow Transplant 2015; 50: 1424–1431.
Wolff SN . Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation. Bone Marrow Transplant 2002; 29: 545–552.
Page KM, Zhang L, Mendizabal A, Wease S, Carter S, Gentry T et al. Total colony-forming units are a strong, independent predictor of neutrophil and platelet engraftment after unrelated umbilical cord blood transplantation: a single-center analysis of 435 cord blood transplants. Biol Blood Marrow Transplant 2011; 17: 1362–1374.
Terakura S, Azuma E, Murata M, Kumamoto T, Hirayama M, Atsuta Y et al. Hematopoietic engraftment in recipients of unrelated donor umbilical cord blood is affected by the CD34+ and CD8+ cell doses. Biol Blood Marrow Transplant 2007; 13: 822–830.
Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337: 373–381.
Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100: 1611–1618.
Scaradavou A, Smith KM, Hawke R, Schaible A, Abboud M, Kernan NA et al. Cord blood units with low CD34+ cell viability have a low probability of engraftment after double unit transplantation. Biol Blood Marrow Transplant 2010; 16: 500–508.
Fowler DH, Gress RE . Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. Leuk Lymphoma 2000; 38: 221–234.
Martin PJ, Hansen JA, Buckner CD, Sanders JE, Deeg HJ, Stewart P et al. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 1985; 66: 664–672.
Ildstad ST, Wren SM, Bluestone JA, Barbieri SA, Stephany D, Sachs DH . Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10+B10.D2——B10). J Immunol 1986; 136: 28–33.
Kernan NA, Flomenberg N, Dupont B, O'Reilly RJ . Graft rejection in recipients of T-cell-depleted HLA-nonidentical marrow transplants for leukemia. Identification of host-derived antidonor allocytotoxic T lymphocytes. Transplantation 1987; 43: 842–847.
Champlin R, Ho W, Gajewski J, Feig S, Burnison M, Holley G et al. Selective depletion of CD8+ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Blood 1990; 76: 418–423.
Martin PJ . Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans. J Exp Med 1993; 178: 703–712.
Martin PJ, Rowley SD, Anasetti C, Chauncey TR, Gooley T, Petersdorf EW et al. A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients. Blood 1999; 94: 2192–2199.
Imahashi N, Inamoto Y, Ito M, Koyama D, Goto T, Onodera K et al. Clinical significance of hemophagocytosis in BM clot sections during the peri-engraftment period following allogeneic hematopoietic SCT. Bone Marrow Transplant 2012; 47: 387–394.
Takagi S, Masuoka K, Uchida N, Ishiwata K, Araoka H, Tsuji M et al. High incidence of haemophagocytic syndrome following umbilical cord blood transplantation for adults. Br J Haematol 2009; 147: 543–553.
Bode SF, Lehmberg K, Maul-Pavicic A, Vraetz T, Janka G, Stadt UZ et al. Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis. Arthritis Res Ther 2012; 14: 213.
Nishiwaki S, Nakayama T, Murata M, Nishida T, Sugimoto K, Saito S et al. Dexamethasone palmitate successfully attenuates hemophagocytic syndrome after allogeneic stem cell transplantation: macrophage-targeted steroid therapy. Int J Hematol 2012; 95: 428–433.
Abdelkefi A, Ben Jamil W, Torjman L, Ladeb S, Ksouri H, Lakhal A et al. Hemophagocytic syndrome after hematopoietic stem cell transplantation: a prospective observational study. Int J Hematol 2009; 89: 368–373.
Fukunaga A, Nakamura F, Yoshinaga N, Inano S, Maruyama W, Hirata H et al. Successful treatment with combined chemotherapy of two adult cases of hemophagocytic lymphohistiocytosis in recipients of umbilical cord blood cell transplantation. Int J Hematol 2011; 93: 551–554.
Ohashi H, Kato C, Fukami S, Saito H, Hamaguchi M . Leukemic relapse in the central nervous system after allogeneic stem cell transplantation with complete remission in the bone marrow and donor-type chimerism: report of two cases. Am J Hematol 2005; 79: 142–146.
Imashuku S . Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol 1997; 66: 135–151.
Nishiwaki S, Terakura S, Ito M, Goto T, Seto A, Watanabe K et al. Impact of macrophage infiltration of skin lesions on survival after allogeneic stem cell transplantation: a clue to refractory graft-versus-host disease. Blood 2009; 114: 3113–3116.
Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 2011; 121: 985–997.
Murphy WJ, Kumar V, Bennett M . Acute rejection of murine bone marrow allografts by natural killer cells and T cells. Differences in kinetics and target antigens recognized. J Exp Med 1987; 166: 1499–1509.
Mattsson J, Ringden O, Storb R . Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2008; 14: 165–170.
Raff RF, Deeg HJ, Loughran TP Jr, Graham TC, Aprile JA, Sale GE et al. Characterization of host cells involved in resistance to marrow grafts in dogs transplanted from unrelated DLA-nonidentical donors. Blood 1986; 68: 861–868.
Yankelevich B, Knobloch C, Nowicki M, Dennert G . A novel cell type responsible for marrow graft rejection in mice. T cells with NK phenotype cause acute rejection of marrow grafts. J Immunol 1989; 142: 3423–3430.
Abe Y, Choi I, Hara K, Matsushima T, Nishimura J, Inaba S et al. Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29: 799–801.
Sreedharan A, Bowyer S, Wallace CA, Robertson MJ, Schmidt K, Woolfrey AE et al. Macrophage activation syndrome and other systemic inflammatory conditions after BMT. Bone Marrow Transplant 2006; 37: 629–634.
Kobayashi R, Tanaka J, Hashino S, Ota S, Torimoto Y, Kakinoki Y et al. Etoposide-containing conditioning regimen reduces the occurrence of hemophagocytic lymphohistiocytosis after SCT. Bone Marrow Transplant 2014; 49: 254–257.
Filipovich A . Hematopoietic cell transplantation for correction of primary immunodeficiencies. Bone Marrow Transplant 2008; 42: S49–S52.
Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC et al. Transplantation outcomes for severe combined immunodeficiency, 2000–2009. N Engl J Med 2014; 371: 434–446.
Koyama M, Hashimoto D, Nagafuji K, Eto T, Ohno Y, Aoyama K et al. Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning. Bone Marrow Transplant 2014; 49: 110–115.
Baron F, Frere P, Baudoux E, Schaaf-Lafontaine N, Fillet G, Beguin Y . Low incidence of acute graft-versus-host disease after non-myeloablative stem cell transplantation with CD8-depleted peripheral blood stem cells: an update. Haematologica 2003; 88: 835–837.
Cao TM, Shizuru JA, Wong RM, Sheehan K, Laport GG, Stockerl-Goldstein KE et al. Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose. Blood 2005; 105: 2300–2306.
Ishida H, Yoshida H, Yoshihara T, Ito M, Morimoto A . Origin of macrophages involved in the development of allogeneic hematopoietic stem cell transplantation-associated hemophagocytic syndrome: observations on a patient with juvenile myelomonocytic leukemia. Bone Marrow Transplant 2007; 40: 701–703.
Tanaka T, Matsubara H, Adachi S, Chang H, Fujino H, Higashi Y et al. Second transplantation from HLA 2-loci-mismatched mother for graft failure due to hemophagocytic syndrome after cord blood transplantation. Int J Hematol 2004; 80: 467–469.
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Kawashima, N., Terakura, S., Nishiwaki, S. et al. Increase of bone marrow macrophages and CD8+ T lymphocytes predict graft failure after allogeneic bone marrow or cord blood transplantation. Bone Marrow Transplant 52, 1164–1170 (2017). https://doi.org/10.1038/bmt.2017.58
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DOI: https://doi.org/10.1038/bmt.2017.58
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