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Journal of Pediatric Biochemistry 2015; 05(04): 115-119
DOI: 10.1055/s-0036-1572322
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Cell Manipulation in Pediatric Haploidentical Stem Cell Transplantation: State of the Art

Manuela Tumino
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
,
Antonio Marzollo
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
,
Maria Vittoria Gazzola
2   Stem Cell Transplantation Laboratory, University of Padova, Padova PD, Italy
,
Elisabetta Calore
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
,
Chiara Mainardi
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
,
Marta Pillon
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
,
Roberta Destro
2   Stem Cell Transplantation Laboratory, University of Padova, Padova PD, Italy
,
Maria Gabelli
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
,
Aurora Strano
2   Stem Cell Transplantation Laboratory, University of Padova, Padova PD, Italy
,
Matteo Barioni
2   Stem Cell Transplantation Laboratory, University of Padova, Padova PD, Italy
,
Chiara Messina
1   Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, University of Padova, Padova PD, Italy
› Author Affiliations
Further Information

Publication History

14 December 2015

30 December 2015

Publication Date:
09 February 2016 (online)

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Abstract

Haploidentical transplantation in children can extend the opportunity for transplantation to almost every patient lacking a human leukocyte antigen (HLA)–matched donor and offer this treatment to every child with an otherwise incurable disease. Although initial attempts were associated with a high transplant-related mortality, recent insights into the biology of haploidentical transplantation, the availability of effective ex vivo large-scale graft-manipulation technology, and improved supportive care strategies have led to significantly better outcomes. Concurrently, the indication for haploidentical transplantation has been extended, including different malignant and nonmalignant conditions. Worldwide donor registries include mainly donors of Caucasian origin. Patients of non-Caucasian origin have a lower chance of finding a suitable unrelated donor. Haploidentical transplantation allows the treatment of children independently of their ethnic background in a timely fashion. One of the major advantages of using a related donor is the possibility of collecting or generating additional cellular products from the same donor to open the possibility of enhancing both the antitumor effects of the graft and the immunologic reconstitution after transplantation.

Keywords

haploidentical transplantation - graft manipulation - pediatric diseases
 

  • References

  • 1 Sasazuki T, Juji T, Morishima Y , et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N Engl J Med 1998; 339 (17) 1177-1185
    CrossrefPubMedSearch in Google Scholar
  • 2 Petersdorf EW, Gooley TA, Anasetti C , et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 1998; 92 (10) 3515-3520
    PubMedSearch in Google Scholar
  • 3 Morishima Y, Sasazuki T, Inoko H , et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood 2002; 99 (11) 4200-4206
    CrossrefPubMedSearch in Google Scholar
  • 4 Morishima Y, Yabe T, Matsuo K , et al; Japan Marrow Donor Program. Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. Biol Blood Marrow Transplant 2007; 13 (3) 315-328
    CrossrefPubMedSearch in Google Scholar
  • 5 Flomenberg N, Baxter-Lowe LA, Confer D , et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 2004; 104 (7) 1923-1930
    CrossrefPubMedSearch in Google Scholar
  • 6 Lee SJ, Klein J, Haagenson M , et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110 (13) 4576-4583
    CrossrefPubMedSearch in Google Scholar
  • 7 Shaw BE, Gooley TA, Malkki M , et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110 (13) 4560-4566
    CrossrefPubMedSearch in Google Scholar
  • 8 Fürst D, Müller C, Vucinic V , et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood 2013; 122 (18) 3220-3229
    CrossrefPubMedSearch in Google Scholar
  • 9 Petersdorf EW, Malkki M, Hsu K , et al; International Histocompatibility Working Group in Hematopoietic Cell Transplantation. 16th IHIW: international histocompatibility working group in hematopoietic cell transplantation. Int J Immunogenet 2013; 40 (1) 2-10
    PubMedSearch in Google Scholar
  • 10 Pidala J, Lee SJ, Ahn KW , et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 2014; 124 (16) 2596-2606
    CrossrefPubMedSearch in Google Scholar
  • 11 Petersdorf EW, Malkki M, Gooley TA, Martin PJ, Guo Z. MHC haplotype matching for unrelated hematopoietic cell transplantation. PLoS Med 2007; 4 (1) e8
    CrossrefPubMedSearch in Google Scholar
  • 12 Morishima S, Ogawa S, Matsubara A , et al; Japan Marrow Donor Program. Impact of highly conserved HLA haplotype on acute graft-versus-host disease. Blood 2010; 115 (23) 4664-4670
    CrossrefPubMedSearch in Google Scholar
  • 13 Kawase T, Morishima Y, Matsuo K , et al; Japan Marrow Donor Program. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood 2007; 110 (7) 2235-2241
    CrossrefPubMedSearch in Google Scholar
  • 14 Pidala J, Wang T, Haagenson M , et al. Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality. Blood 2013; 122 (22) 3651-3658
    CrossrefPubMedSearch in Google Scholar
  • 15 Fleischhauer K, Shaw BE, Gooley T , et al; International Histocompatibility Working Group in Hematopoietic Cell Transplantation. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 2012; 13 (4) 366-374
    CrossrefPubMedSearch in Google Scholar
  • 16 Morishima Y, Kashiwase K, Matsuo K , et al; Japan Marrow Donor Program. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood 2015; 125 (7) 1189-1197
    CrossrefPubMedSearch in Google Scholar
  • 17 Reisner Y, Ravid A, Sharon N. Use of soybean agglutinin for the separation of mouse B and T lymphocytes. Biochem Biophys Res Commun 1976; 72 (4) 1585-1591
    CrossrefPubMedSearch in Google Scholar
  • 18 Reisner Y, Itzicovitch L, Meshorer A, Sharon N. Hemopoietic stem cell transplantation using mouse bone marrow and spleen cells fractionated by lectins. Proc Natl Acad Sci U S A 1978; 75 (6) 2933-2936
    CrossrefPubMedSearch in Google Scholar
  • 19 Reisner Y, Kapoor N, O'Reilly RJ, Good RA. Allogeneic bone marrow transplantation using stem cells fractionated by lectins: VI, in vitro analysis of human and monkey bone marrow cells fractionated by sheep red blood cells and soybean agglutinin. Lancet 1980; 2 (8208–8209) 1320-1324
    PubMedSearch in Google Scholar
  • 20 Reisner Y, Kapoor N, Kirkpatrick D , et al. Transplantation for acute leukaemia with HLA-A and B nonidentical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet 1981; 2 (8242) 327-331
    PubMedSearch in Google Scholar
  • 21 Reisner Y, Kapoor N, Kirkpatrick D , et al. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood 1983; 61 (2) 341-348
    PubMedSearch in Google Scholar
  • 22 Jabado N, Le Deist F, Cant A , et al. Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection. Pediatrics 1996; 98 (3, Pt 1): 420-428
    PubMedSearch in Google Scholar
  • 23 Ash RC, Horowitz MM, Gale RP , et al. Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion. Bone Marrow Transplant 1991; 7 (6) 443-452
    PubMedSearch in Google Scholar
  • 24 Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 2001; 166 (2) 973-981
    CrossrefPubMedSearch in Google Scholar
  • 25 Reisner Y, Ben-Bassat I, Douer D, Kaploon A, Schwartz E, Ramot B. Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation. Proc Natl Acad Sci U S A 1986; 83 (11) 4012-4015
    CrossrefPubMedSearch in Google Scholar
  • 26 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 (6) 842-847
    CrossrefPubMedSearch in Google Scholar
  • 27 Aversa F, Tabilio A, Terenzi A , et al. Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 1994; 84 (11) 3948-3955
    PubMedSearch in Google Scholar
  • 28 Lapidot T, Terenzi A, Singer TS, Salomon O, Reisner Y. Enhancement by dimethyl myleran of donor type chimerism in murine recipients of bone marrow allografts. Blood 1989; 73 (7) 2025-2032
    PubMedSearch in Google Scholar
  • 29 Terenzi A, Lubin I, Lapidot T , et al. Enhancement of T cell-depleted bone marrow allografts in mice by thiotepa. Transplantation 1990; 50 (4) 717-720
    CrossrefPubMedSearch in Google Scholar
  • 30 Schwartz E, Lapidot T, Gozes D, Singer TS, Reisner Y. Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors. J Immunol 1987; 138 (2) 460-465
    PubMedSearch in Google Scholar
  • 31 Lapidot T, Singer TS, Salomon O, Terenzi A, Schwartz E, Reisner Y. Booster irradiation to the spleen following total body irradiation. A new immunosuppressive approach for allogeneic bone marrow transplantation. J Immunol 1988; 141 (8) 2619-2624
    PubMedSearch in Google Scholar
  • 32 Cobbold SP, Martin G, Qin S, Waldmann H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature 1986; 323 (6084) 164-166
    Search in Google Scholar
  • 33 Lapidot T, Lubin I, Terenzi A, Faktorowich Y, Erlich P, Reisner Y. Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity. Proc Natl Acad Sci U S A 1990; 87 (12) 4595-4599
    CrossrefPubMedSearch in Google Scholar
  • 34 Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1995; 1 (12) 1268-1273
    CrossrefPubMedSearch in Google Scholar
  • 35 Rachamim N, Gan J, Segall H , et al. Tolerance induction by “megadose” hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation 1998; 65 (10) 1386-1393
    CrossrefPubMedSearch in Google Scholar
  • 36 Reisner Y, Gur H, Reich-Zeliger S, Martelli MF, Bachar-Lustig E. Hematopoietic stem cell transplantation across major genetic barriers: tolerance induction by megadose CD34 cells and other veto cells. Ann N Y Acad Sci 2003; 996: 72-79
    CrossrefPubMedSearch in Google Scholar
  • 37 Aversa F, Tabilio A, Velardi A , et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998; 339 (17) 1186-1193
    CrossrefPubMedSearch in Google Scholar
  • 38 Aversa F, Terenzi A, Tabilio A , et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23 (15) 3447-3454
    CrossrefPubMedSearch in Google Scholar
  • 39 Chen X, Hale GA, Barfield R , et al. Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol 2006; 135 (4) 524-532
    CrossrefPubMedSearch in Google Scholar
  • 40 Dufort G, Pisano S, Incoronato A , et al. Feasibility and outcome of haploidentical SCT in pediatric high-risk hematologic malignancies and Fanconi anemia in Uruguay. Bone Marrow Transplant 2012; 47 (5) 663-668
    CrossrefPubMedSearch in Google Scholar
  • 41 Klingebiel T, Cornish J, Labopin M , et al; Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood 2010; 115 (17) 3437-3446
    CrossrefPubMedSearch in Google Scholar
  • 42 Norell H, Moretta A, Silva-Santos B, Moretta L. At the bench: preclinical rationale for exploiting NK cells and γδ T lymphocytes for the treatment of high-risk leukemias. J Leukoc Biol 2013; 94 (6) 1123-1139
    CrossrefPubMedSearch in Google Scholar
  • 43 Handgretinger R. Negative depletion of CD3(+) and TcRαβ(+) T cells. Curr Opin Hematol 2012; 19 (6) 434-439
    CrossrefPubMedSearch in Google Scholar
  • 44 Bertaina A, Merli P, Rutella S , et al. HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 2014; 124 (5) 822-826
    CrossrefPubMedSearch in Google Scholar
  • 45 Zecca M, Strocchio L, Pagliara D , et al. HLA-haploidentical T cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia. Biol Blood Marrow Transplant 2014; 20 (4) 571-576
    CrossrefPubMedSearch in Google Scholar
  • 46 Kanakry CG, Ganguly S, Zahurak M , et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med 2013; 5 (211) 211ra157
    CrossrefPubMedSearch in Google Scholar
  • 47 Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood 2001; 98 (12) 3456-3464
    CrossrefPubMedSearch in Google Scholar
  • 48 Luznik L, O'Donnell PV, Symons HJ , et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14 (6) 641-650
    CrossrefPubMedSearch in Google Scholar
  • 49 Bolaños-Meade J, Fuchs EJ, Luznik L , et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 2012; 120 (22) 4285-4291
    CrossrefPubMedSearch in Google Scholar
  • 50 Jaiswal SR, Chakrabarti A, Chatterjee S , et al. Haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transplant . pii: S1083-8791(15)00737-5. doi:10.1016/j.bbmt.2015.11.010
    PubMed
  • 51 Brunstein CG, Fuchs EJ, Carter SL , et al; Blood and Marrow Transplant Clinical Trials Network. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118 (2) 282-288
    CrossrefPubMedSearch in Google Scholar