[en] We investigated whether pretransplantation immunosuppression with canine-specific rabbit antithymocyte globulin (ATG), combined with a suboptimal dose of 1 Gy of total body irradiation (TBI), would permit engraftment of canine dog leukocyte antigen-identical marrow. Cumulative ATG doses of 2 to 5 mg/kg produced a T-cell depletion of 1 log in the peripheral blood and 50% in the lymph nodes. Serum levels of ATG peaked on days 4 to 6 after initiation of therapy and became undetectable by day 13 as a result of canine antibody responses to ATG. ATG prolonged allogeneic skin graft survival to 14 days (n = 5), compared with 8 days in control dogs (P = .0003). Five dogs were given marrow transplants after ATG (3.5-5 mg/kg) and 1 Gy of TBI. Posttransplantation immunosuppression consisted of mycophenolate mofetil and cyclosporine. All dogs showed initial engraftment, with maximum donor chimerism levels of 25%. However, only 1 dog achieved sustained engraftment, and 4 rejected their grafts. The duration of engraftment ranged from 8 to > or = 36 weeks (median, 11 weeks), and this is comparable to that in 6 historical controls not given ATG (range, 3-12 weeks; median, 10 weeks; P = .20). The total nucleated cell doses in the marrow grafts had the highest correlation coefficient with the duration of engraftment: 0.82 (P = .09). We concluded that administering ATG before an otherwise suboptimal conditioning dose of 1 Gy of TBI failed to secure uniform stable hematopoietic engraftment.
Disciplines :
Hematology
Author, co-author :
Diaconescu, Razvan
Little, Marie-Terese
Leisenring, Wendy
Yunusov, Murad
Hogan, William J
Sorror, Mohamed L
Baron, Frédéric ; Université de Liège - ULiège > Département des sciences cliniques > GIGA-R : Hématologie - Département des sciences cliniques
Storb, Rainer
Language :
English
Title :
What role is there for antithymocyte globulin in allogeneic nonmyeloablative canine hematopoietic cell transplantation?
Publication date :
2005
Journal title :
Biology of Blood and Marrow Transplantation
ISSN :
1083-8791
eISSN :
1523-6536
Publisher :
Carden Jennings Publishing, Charlottesville, United States - Virginia
R. Storb C. Yu J.L. Wagner et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation Blood 89 1997 3048-3054
P.A. McSweeney D. Niederwieser J.A. Shizuru et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects Blood 97 2001 3390-3400
M.B. Maris D. Niederwieser B.M. Sandmaier et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies Blood 102 2003 2021-2030
D. Niederwieser M. Maris J.A. Shizuru et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases Blood 101 2003 1620-1629
R. Storb C. Yu T. Barnett et al. Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation Blood 94 1999 1131-1136
W.J. Hogan M.-T. Little E. Zellmer et al. Postgrafting immunosuppression with sirolimus and cyclosporine facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before marrow transplantation from DLA-identical littermates Biol Blood Marrow Transplant 9 2003 489-495
C.-Q. Xun M.-T. Little E. Zellmer et al. What role for FTY720, a novel immunosuppressive agent, in canine nonmyeloablative hematopoietic stem cell transplantation? Transplantation 73 2002 310-313
R. Storb C. Yu J.M. Zaucha et al. Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant Blood 94 1999 2523-2529
L. Genestier S. Fournel M. Flacher O. Assossou J.P. Revillard N. Bonnefoy-Berard Induction of Fas (Apo-1, CD95)-mediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins Blood 91 1998 2360-2368
S. Slavin A. Nagler E. Naparstek et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases Blood 91 1998 756-763
R. Storb R. Etzioni C. Anasetti et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia Blood 84 1994 941-949
R. Storb P.L. Weiden K.M. Sullivan et al. Second marrow transplants in patients with aplastic anemia rejecting the first graft: Use of a conditioning regimen including cyclophosphamide and antithymocyte globulin Blood 70 1987 116-121
T.R. Spitzer S. McAfee R. Sackstein et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies Biol Blood Marrow Transplant 6 2000 309-320
C. Grosskreutz V. Ross E. Scigliano S. Fruchtman L. Isola Low-dose total body irradiation, fludarabine, and antithymocyte globulin conditioning for nonmyeloablative allogeneic transplantation Biol Blood Marrow Transplant 9 2003 453-459
J.L. Wagner R.C. Burnett S.A. DeRose L.V. Francisco R. Storb E.A. Ostrander Histocompatibility testing of dog families with highly polymorphic microsatellite markers Transplantation 62 1996 876-877
R.C. Burnett L.V. Francisco S.A. DeRose R. Storb E.A. Ostrander Identification and characterization of a highly polymorphic microsatellite marker within the canine MHC class I region Mamm Genome 6 1995 684-685
J.L. Wagner J.D. Works R. Storb DLA-DRB1 and DLA-DQB1 histocompatibility typing by PCR-SSCP and sequencing [brief communication] Tissue Antigens 52 1998 397-401
J.M. Zaucha E. Zellmer G. Georges et al. G-CSF-mobilized peripheral blood mononuclear cells added to marrow facilitates engraftment in nonmyeloablated canine recipients: CD3 cells are required Biol Blood Marrow Transplant 7 2001 613-619
P.F. Moore P.V. Rossitto D.M. Danilenko J.J. Wielenga R.F. Raff E. Severns Monoclonal antibodies specific for canine CD4 and CD8 define functional T-lymphocyte subsets and high density expression of CD4 by canine neutrophils Tissue Antigens 40 1992 75-85
P.A. McSweeney K.A. Rouleau P.M. Wallace et al. Characterization of monoclonal antibodies that recognize canine CD34 Blood 91 1998 1977-1986
R.F. Raff H.J. Deeg V.T. Farewell S. DeRose R. Storb The canine major histocompatibility complex. Population study of DLA-D alleles using a panel of homozygous typing cells Tissue Antigens 21 1983 360-373
X. Preville M. Flacher B. LeMauff et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model Transplantation 71 2001 460-468
H.D. Ochs R. Storb E.D. Thomas et al. Immunologic reactivity in canine marrow graft recipients J Immunol 113 1974 1039-1057
M.Y. Yunusov G.E. Georges R. Storb et al. FLT3 ligand promotes engraftment of allogeneic hematopoietic stem cells without significant graft-versus-host disease Transplantation 75 2003 933-940
C. Yu E. Ostrander E. Bryant R. Burnett R. Storb Use of (CA)n polymorphisms to determine the origin of blood cells after allogeneic canine marrow grafting Transplantation 58 1994 701-706
R. Storb R.F. Raff F.R. Appelbaum et al. What radiation dose for DLA-identical canine marrow grafts? Blood 72 1988 1300-1304
R. Storb R.F. Raff F.R. Appelbaum et al. Comparison of fractionated to single-dose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts Blood 74 1989 1139-1143
N.C. Gorin M. Labopin V. Rocha et al. Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow Blood 102 2003 3043-3051
J. Sierra B. Storer J.A. Hansen et al. Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: The effect of leukemic burden, donor HLA-matching, and marrow cell dose Blood 89 1997 4226-4235
J. Finke H. Bertz C. Schmoor et al. Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin Br J Haematol 111 2000 303-313
M. Schleuning W. Gunther J. Tischer G. Ledderose H.J. Kolb Dose-dependent effects of in vivo antithymocyte globulin during conditioning for allogeneic bone marrow transplantation from unrelated donors in patients with chronic phase CML Bone Marrow Transplant 32 2003 243-250
E.K. Waller A.A. Langston S. Lonial et al. Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation Biol Blood Marrow Transplant 9 2003 460-471
C. Wakabayashi T. Adachi J. Wienands T. Tsubata A distinct signaling pathway used by the IgG-containing B cell antigen receptor Science 298 2002 2392-2395