Comparison of T-Cell-Depleted BMT and PBPCT with Respect to Chimerism, Graft Rejection, and Leukemic Relapse

We have investigated which T cell subclass defined by cytolysis with monoclonal anti-Lyt-1.2 and anti-Lyt-2.2 antibodies is required to adoptively transfer the ability to reject skin grafts. B6.Thy-1.1 spleen cells immune to graft antigens were fractionated with antibody plus C' and transferred to adult thymectomized, irradiated, bone marrow-reconstituted (ATXBM) B6.Thy-1.2 hosts that were simultaneously grafted with BALB.B skin. We found that when the ATXBM hosts were used 6 wk after irradiation and marrow reconstitution, both Lyt-1-depleted and Lyt-2-depleted immune spleen cells could transfer the ability to promptly reject skin grafts. However, such ATXBM recipients of Lyt-2-depleted cells that had rejected skin grafts were found to contain graft-specific CTL that were largely of host (B6.Thy-1.2) origin. When ATXBM hosts were used for the experiment 1 wk after irradiation and marrow reconstitution, no host-derived graft-specific CTL could be detected. However, graft rejection occurred in recipients of anti-Lyt-1- or anti-Lyt-2 plus C'-treated immune cells and specific CTL were generated from spleen cells of both groups. Thus, in the absence of a host-derived response, adoptively transferred immune Lyt-2+ cells, either resistant to, or that escaped from, antibody plus C' treatment, are able to expand in response to the antigenic stimulus provided by the graft. A more complete elimination of specific T cell subclasses is therefore needed to assess the relative contribution of a particular subset to the graft rejection process.

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The Significance of Non–T-Cell Pathways in Graft Rejection: Implications for Transplant Tolerance

Transplantation Journal ◽

10.1097/tp.0b013e3181efcfe9 ◽

2010 ◽

Vol 90 (10) ◽

pp. 1043-1047 ◽

Cited By ~ 23

Author(s):

Xian Chang Li

Keyword(s):

T Cell ◽

Graft Rejection ◽

Transplant Tolerance

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Analysis of immunoglobulin and T-cell receptor gene deficiency in graft rejection by gene expression profiles1

Transplantation Journal ◽

10.1097/01.tp.0000113803.45613.f8 ◽

2004 ◽

Vol 77 (4) ◽

pp. 580-586 ◽

Cited By ~ 4

Author(s):

Rachel A. DeFina ◽

Yurong Liang ◽

Hongzhen He ◽

Kathleen J. Haley ◽

Kenneth Christopher ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

T Cell Receptor ◽

Graft Rejection ◽

Receptor Gene ◽

Cell Receptor ◽

Gene Deficiency ◽

T Cell Receptor Gene ◽

Cell Receptor Gene

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Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

Blood ◽

10.1182/blood.v90.12.4743 ◽

1997 ◽

Vol 90 (12) ◽

pp. 4743-4748 ◽

Cited By ~ 79

Author(s):

Nada Jabado ◽

Elizabeth R. de Graeff-Meeder ◽

Marina Cavazzana-Calvo ◽

Elie Haddad ◽

Françoise Le Deist ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

T Cell ◽

Graft Rejection ◽

Hemophagocytic Lymphohistiocytosis ◽

Marrow Transplantation ◽

Conditioning Regimen ◽

Free Survival ◽

Familial Hemophagocytic Lymphohistiocytosis ◽

Disease Free

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

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Involvement of Donor T-Cell Cytotoxic Effector Mechanisms in Preventing Allogeneic Marrow Graft Rejection

Blood ◽

10.1182/blood.v92.6.2177 ◽

1998 ◽

Vol 92 (6) ◽

pp. 2177-2181 ◽

Cited By ~ 68

Author(s):

Paul J. Martin ◽

Yoshiki Akatsuka ◽

Michael Hahne ◽

George Sale

Keyword(s):

T Cells ◽

T Cell ◽

Graft Rejection ◽

Fas Ligand ◽

Conditioning Regimen ◽

Marrow Graft ◽

Hematopoietic Stem ◽

Cd8 Cells ◽

Allogeneic Marrow ◽

Cytotoxic Effector

Abstract Donor CD8 cells play a pivotal role in preventing allogeneic marrow graft rejection, possibly by generating cytotoxic effectors needed to eliminate recipient T cells remaining after the pretransplant conditioning regimen or by producing cytokines needed to support the growth and differentiation of hematopoietic stem cells. In the present study, we assessed the role of donor T-cell cytotoxic effector function as a mechanism for eliminating recipient CD8 cells that cause marrow graft rejection in mice. The ability to prevent rejection was minimally affected by the presence of a defect in Fas ligand binding or by the absence of granzyme B but was severely affected by the absence of perforin. Doubly mutant perforin-deficient, Fas ligand-defective CD8 cells were completely unable to prevent rejection. Our results indicate first that recipient CD8 effectors responsible for causing marrow graft rejection are sensitive to cytotoxicity mediated by both perforin- and Fas-ligand-dependent mechanisms, and second that donor T cells must have at least one functional cytotoxic mechanism to prevent allogeneic marrow graft rejection. © 1998 by The American Society of Hematology.

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HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: analysis of survival and remission duration

Blood ◽

10.1182/blood.v72.6.1978.1978 ◽

1988 ◽

Vol 72 (6) ◽

pp. 1978-1984 ◽

Cited By ~ 44

Author(s):

PJ Martin ◽

RA Clift ◽

LD Fisher ◽

CD Buckner ◽

JA Hansen ◽

...

Keyword(s):

T Cell ◽

Chronic Myelogenous Leukemia ◽

Marrow Transplantation ◽

Proportional Hazards ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Time Interval ◽

Related Factors ◽

Relapse Risk ◽

Leukemic Relapse

Abstract Results of HLA-identical allogeneic marrow transplantation were analyzed for 66 patients with accelerated-phase chronic myelogenous leukemia (CML). Multivariate proportional hazards regression models were used to determine disease-related and transplant-related factors associated with posttransplant mortality and relapse. The projected 5- year survival rate was estimated at 18% by the product-limit method. The major causes of death were interstitial pneumonia, infection, and relapse. Splenomegaly at initial diagnosis and longer time interval from diagnosis to transplant were associated with decreased overall survival and event-free survival. Sixteen patients have relapsed between 17 and 1,569 days (median, 486) posttransplant. The use of T- cell-depleted marrow and older age of the donor or recipient were associated with an increased probability of leukemic relapse. Ten of the 16 relapses occurred among the 15 patients who received T-cell- depleted marrow. The actuarial relapse risk 2.5 years posttransplant was 100% in patients administered T-cell-depleted marrow as compared with 25% in patients administered unmodified marrow. The data in this report emphasize the increased risks and relatively poor results that occur when marrow transplantation is deferred until after signs of acceleration appear. When compared with results for patients who received transplants during chronic phase, the poor results seen here in patients administered unmodified marrow stem primarily from increased transplant-related mortality rather than increased relapse risk. The strikingly increased relapse rate associated with the use of T-cell depletion would discourage its use for graft-v-host disease prevention in patients who receive transplants for CML.

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Effect of recombinant human macrophage colony-stimulating factor in irradiated murine recipients of T-cell-depleted allogeneic or non- depleted syngeneic bone marrow transplants

Blood ◽

10.1182/blood.v79.6.1636.1636 ◽

1992 ◽

Vol 79 (6) ◽

pp. 1636-1642 ◽

Cited By ~ 10

Author(s):

BR Blazar ◽

SL Aukerman ◽

DA Vallera

Keyword(s):

Bone Marrow ◽

T Cell ◽

Nk Cells ◽

Graft Rejection ◽

Tnf Alpha ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract Recombinant macrophage colony-stimulating factor (rM-CSF), which reacts exclusively with cells of monocyte lineage, was evaluated in the murine bone marrow (BM) transplant setting for in vivo effects on recipient survival, hematologic recovery, and engraftment. Two types of fully allogeneic donors were selected based on the expression (BALB/c), or lack of expression (DBA/1), of hybrid hematopoietic histocompatibility (Hh1) antigens. These antigens are established targets for monocyte and/or natural killer (NK) cell-mediated graft rejection. Irradiated C57BL/6 mice were used as recipients for all experiments. Recipients of T-cell-depleted (TCD) BALB/c BM and a 14-day continuous subcutaneous infusion of 16.8 micrograms/d rM-CSF (n = 30) showed a significant decrease in donor cell engraftment as compared with recipients of donor BM administered pumps delivering saline. These mice administered rM-CSF also displayed significantly reduced levels of circulating leukocytes (predominantly lymphocytes) on day 14 posttransplant (compared with saline controls). Neither engraftment effects nor leukocyte effects were observed when C57BL/6 recipients were administered Hh1 nonexpressing TCD DBA/1 BM cells (n = 30), suggesting that the monocyte/macrophage population is important in long-term alloengraftment in certain donor-recipient strain combinations in which donor Hh1 antigens can serve as target antigens for host effector cells, but are not important in strain combinations in which they are not recognized. Circulating tumor necrosis factor alpha (TNF alpha) levels measured at two time periods during rM-CSF infusion were not elevated. Thus, the reduction in alloengraftment is not likely to be directly related to TNF alpha. However, in vivo elimination of NK cells in the BALB/c into C57BL/6 model prevented the impairment of engraftment mediated by rM-CSF. Thus, rM-CSF-mediated inhibition of alloengraftment is contingent on the presence of host NK cells with antidonor reactivity. Survival was unaffected when rM-CSF was administered in either allogeneic BM transplant model, but was significantly reduced when rM-CSF was administered to C57BL/6 recipients of syngeneic BM transplants. These data are the first analyzing the effects of rM-CSF in murine allogeneic BM transplantation and extend our previous studies using the BALB/c into C57BL/6 model in which in vivo infusions of recombinant granulocyte-macrophage CSF, but not recombinant granulocyte-CSF, lead to decreases in alloengraftment. These data show that rM-CSF-induced stimulation of monocytes may increase BM graft rejection in instances in which NK cells are involved in the rejection process. These data may have future clinical implications for the use of rM-CSF in allogeneic BM transplantation.

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