scholarly journals Enhancement of T-cell-depleted bone marrow allografts in the absence of graft-versus-host disease is mediated by CD8+ CD4- and not by CD8- CD4+ thymocytes

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2406-2411 ◽  
Author(s):  
T Lapidot ◽  
Y Faktorowich ◽  
I Lubin ◽  
Y Reisner
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Sorting ◽  
Radiation Doses ◽  
Peanut Agglutinin ◽  
Graft Versus Host ◽  
Hematopoietic Reconstitution ◽  
Activity Enhancement ◽  
Total Body ◽  
Low Radiation Doses

Transplantation of T-cell-depleted C57BL/6-Nu/Nu (“nude”) bone marrow (BM) into C3H/HeJ recipients, conditioned with 8 Gy total body irradiation plus chemotherapy with the myeloablative drug dimethyl myleran, resulted in poor hematopoietic reconstitution 14 days posttransplant, compared with transplantation with T-cell-depleted BM from normal C57BL/6 donors. Hematopoietic reconstitution of “nude” BM could be improved by the addition of (C57BL/6xC3H/HeJ)F1 thymocytes void of graft-versus-host activity. Enhancement of BM allografting by thymocytes is sensitive to low radiation doses (> or = 5.0 Gy) and can be achieved by transplanting the BM 24 hours before the administration of thymocytes. Fractionation of F1 thymocytes by differential agglutination with peanut agglutinin (PNA) and by fluorescence activated cell sorting showed that this hematopoietic enhancing activity is enriched in the unagglutinated (PNA-) thymocyte fraction and is mediated by PNA- CD8+ and not by PNA- CD4+ thymocytes.

scholarly journals Enhancement of T-cell-depleted bone marrow allografts in the absence of graft-versus-host disease is mediated by CD8+ CD4- and not by CD8- CD4+ thymocytes

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2406-2411 ◽  
Author(s):  
T Lapidot ◽  
Y Faktorowich ◽  
I Lubin ◽  
Y Reisner
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Sorting ◽  
Radiation Doses ◽  
Peanut Agglutinin ◽  
Graft Versus Host ◽  
Hematopoietic Reconstitution ◽  
Activity Enhancement ◽  
Total Body ◽  
Low Radiation Doses

Abstract Transplantation of T-cell-depleted C57BL/6-Nu/Nu (“nude”) bone marrow (BM) into C3H/HeJ recipients, conditioned with 8 Gy total body irradiation plus chemotherapy with the myeloablative drug dimethyl myleran, resulted in poor hematopoietic reconstitution 14 days posttransplant, compared with transplantation with T-cell-depleted BM from normal C57BL/6 donors. Hematopoietic reconstitution of “nude” BM could be improved by the addition of (C57BL/6xC3H/HeJ)F1 thymocytes void of graft-versus-host activity. Enhancement of BM allografting by thymocytes is sensitive to low radiation doses (> or = 5.0 Gy) and can be achieved by transplanting the BM 24 hours before the administration of thymocytes. Fractionation of F1 thymocytes by differential agglutination with peanut agglutinin (PNA) and by fluorescence activated cell sorting showed that this hematopoietic enhancing activity is enriched in the unagglutinated (PNA-) thymocyte fraction and is mediated by PNA- CD8+ and not by PNA- CD4+ thymocytes.

Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow Via In Utero or Postnatal Transfer

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3949-3959 ◽  
Author(s):  
Bruce R. Blazar ◽  
Patricia A. Taylor ◽  
Ron McElmurry ◽  
Lina Tian ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adoptive Transfer ◽  
In Utero ◽  
Allogeneic Bone ◽  
Severe Combined Immune Deficiency ◽  
Graft Versus Host ◽  
In Utero Transplantation ◽  
Total Body

Abstract Although in utero transplantation (IUT) has been shown to be effective in treating human severe combined immune deficiency (SCID), the relative merit of IUT as compared with postnatal bone marrow transplantation (BMT) for SCID is unknown. Therefore, comparative studies were undertaken in mice to determine the engraftment outcome in these two settings. Because T-cell depletion (TCD) reduces graft-versus-host disease (GVHD) severity but compromises alloengraftment, studies were performed with TCD or non-TCD BM and GVHD risk was assessed using a tissue scoring system and by the adoptive transfer of splenocytes from engrafted mice into secondary recipients. Non-SCID recipients received pre-BMT irradiation to simulate those circumstances in which conditioning is required for alloengraftment. IUT recipients of non-TCD and especially TCD BM cells in general had higher levels of donor T-cell and myeloid peripheral blood (PB) engraftment than nonconditioned SCID recipients. Increased TCD or non-TCD BM cell numbers in adult SCID recipients resulted in similar levels of PB engraftment as IUT recipients. However, under these conditions, mean GVHD scores were higher than in IUT recipients. The majority of adoptive transfer recipients of splenocytes from IUT recipients were GVHD-free, consistent with the in vitro evidence of tolerance to host alloantigens. Total body irradiation (TBI)-treated mice that had the highest engraftment had evidence of thymic damage as denoted by a higher proportion of thymic and splenic T cells with a memory phenotype as compared with IUT recipients. IUT mice had vigorous thymic reconstitution by 3 weeks of age. Our data indicate that IUT has a number of advantages as compared with postnatal BMT. Future studies examining the fine specificity of immunoreconstitution in IUT versus postnatal BMT are indicated.

Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow Via In Utero or Postnatal Transfer

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3949-3959 ◽  
Author(s):  
Bruce R. Blazar ◽  
Patricia A. Taylor ◽  
Ron McElmurry ◽  
Lina Tian ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adoptive Transfer ◽  
In Utero ◽  
Allogeneic Bone ◽  
Severe Combined Immune Deficiency ◽  
Graft Versus Host ◽  
In Utero Transplantation ◽  
Total Body

Although in utero transplantation (IUT) has been shown to be effective in treating human severe combined immune deficiency (SCID), the relative merit of IUT as compared with postnatal bone marrow transplantation (BMT) for SCID is unknown. Therefore, comparative studies were undertaken in mice to determine the engraftment outcome in these two settings. Because T-cell depletion (TCD) reduces graft-versus-host disease (GVHD) severity but compromises alloengraftment, studies were performed with TCD or non-TCD BM and GVHD risk was assessed using a tissue scoring system and by the adoptive transfer of splenocytes from engrafted mice into secondary recipients. Non-SCID recipients received pre-BMT irradiation to simulate those circumstances in which conditioning is required for alloengraftment. IUT recipients of non-TCD and especially TCD BM cells in general had higher levels of donor T-cell and myeloid peripheral blood (PB) engraftment than nonconditioned SCID recipients. Increased TCD or non-TCD BM cell numbers in adult SCID recipients resulted in similar levels of PB engraftment as IUT recipients. However, under these conditions, mean GVHD scores were higher than in IUT recipients. The majority of adoptive transfer recipients of splenocytes from IUT recipients were GVHD-free, consistent with the in vitro evidence of tolerance to host alloantigens. Total body irradiation (TBI)-treated mice that had the highest engraftment had evidence of thymic damage as denoted by a higher proportion of thymic and splenic T cells with a memory phenotype as compared with IUT recipients. IUT mice had vigorous thymic reconstitution by 3 weeks of age. Our data indicate that IUT has a number of advantages as compared with postnatal BMT. Future studies examining the fine specificity of immunoreconstitution in IUT versus postnatal BMT are indicated.

scholarly journals Different T-cell receptor repertoires between lesions and peripheral blood in acute graft-versus-host disease after allogeneic bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3019-3026 ◽  
Author(s):  
K Kubo ◽  
K Yamanaka ◽  
H Kiyoi ◽  
H Fukutani ◽  
M Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

From the viewpoint of T-cell receptor (TCR) repertoire, we studied the role of T cells in acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. By means of inverse polymerase chain reaction method and DNA sequencing, we analyzed TCR-alpha and -beta transcripts from GVHD lesions and peripheral blood (PB) in a patient with typical GVHD together with PB from donor. At the initial onset of GVHD, V alpha-7 and -19 subfamilies were oligoclonally expanded in the PB compared with those in the oral mucosal lesions. At the second onset, V alpha-2, and V beta-6 subfamilies were more frequently detected in the cutaneous lesion than in the PB. Some TCR transcripts were recurrently found either in the mucosal or cutaneous lesions (or in both) and not in the PB. Furthermore, some of recurrent TCR transcripts in the lesions shared V gene segments and common motifs of complementarity determining region-3. These findings suggested that T cells infiltrating the GVHD lesions recognized a limited kind of antigens presented by patient's tissues with GVHD, and that T-cell repertoire in the GVHD lesions was different from that in the PB.

scholarly journals Pretreatment of murine donor grafts with L-leucyl-L-leucine methyl ester: elimination of graft-versus-host disease without detrimental effects on engraftment

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 798-805 ◽  
Author(s):  
BR Blazar ◽  
DL Thiele ◽  
DA Vallera
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Methyl Ester ◽  
Graft Versus Host Disease ◽  
Host Cells ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host

Abstract Incubation of murine bone marrow and splenocytes with the dipeptide methyl ester, L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), which results in the selective depletion of cytotoxic T cells and their precursors, natural killer cells, and monocytes, completely protected 30 recipients of fully allogeneic donor grafts from lethal graft-versus- host disease (GVHD). These results were comparable with those obtained in 30 recipients of anti-Thy 1.2 plus complement (C')-treated donor marrow. However, in contrast to antibody- and C'-dependent T-cell depletion, which reduces the level of donor cell engraftment in our model system, we did not observe such effects using Leu-Leu-OMe marrow pretreatment. As compared with the 24 H-2 typed recipients of anti-Thy 1.2 + C'-treated donor grafts, the 29 H-2 typed recipients of Leu-Leu- OMe-treated donor grafts had significantly (P less than .001) higher percentages of donor cells (mean = 93% v 74%) and significantly (P less than .001) lower percentages of host cells (mean = 6% v 15%) posttransplantation. In vitro limiting dilution assay (LDA) was performed to assess the comparative efficacy of cytolytic T-lymphocyte (CTL) precursor depletion by Leu-Leu-OMe or anti-Thy 1.2 + C' pretreatment. We observed greater levels of CTL precursor depletion in Leu-Leu-OMe treated as compared with anti-Thy 1.2 + C'-treated bone marrow plus spleen cells (BMS) obtained from nontransplanted mice. This suggests that the in vivo results cannot simply be attributed to a less efficacious functional inactivation of cytolytic T-cell precursors by Leu-Leu-OMe treatment as compared with anti-Thy 1.2 + C' treatment. Immunoreconstitution was similar in recipients of Leu-Leu-OMe-treated grafts and anti-Thy 1.2 + C'-treated grafts 100 days posttransplant. In our opinion, Leu-Leu-OMe marrow pretreatment deserves further investigation as a methodology to achieve GVHD prevention without significantly reducing the propensity toward host cell repopulation.

CD6+ Donor Marrow T-Cell Depletion as the Sole Form of Graft-Versus-Host Disease Prophylaxis in Patients Undergoing Allogeneic Bone Marrow Transplant From Unrelated Donors

2001 ◽  
Vol 19 (4) ◽  
pp. 1152-1159 ◽  
Author(s):  
Robert J. Soiffer ◽  
Edie Weller ◽  
Edwin P. Alyea ◽  
Peter Mauch ◽  
Iain L. Webb ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Bone Marrow Transplant ◽  
Graft Versus Host Disease ◽  
Marrow Transplant ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis. PATIENTS AND METHODS: Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5 Gy (26 points) of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment. RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 × 106/L was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival was 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P = .002), cytomegalovirus seronegative status (P = .04), and early disease status at bone marrow transplant (P = .05) were associated with superior survival. CONCLUSION: CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in an incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD.

scholarly journals Cyclosporin A-Induced Autoimmunity in the Rat: Central versus Peripheral Tolerance

2002 ◽  
Vol 15 (2) ◽  
pp. 81-87 ◽  
Author(s):  
J.G.M.C. Damoiseaux
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cyclosporin A ◽  
Tolerance Induction ◽  
Chronic Phase ◽  
Metastatic Breast ◽  
Autologous Bone Marrow ◽  
Peripheral Tolerance ◽  
Central Tolerance ◽  
Total Body

Cyclosporin A-induced autoimmunity (CsA-AI) is a thymus dependent and T cell-mediated autoimmune disease that is readily induced in rodents (1, 2) and also occurs in humans (3). Induction of CsA-AI requires total body X-irradiation, rescue with syngeneic or autologous bone marrow, and subsequent cyclosporin A (CsA) administration for about 4 weeks (4). Because the induction protocol involves bone marrow transplantation (BMT), CsA-AI is also referred to as syngeneic or autoimmune graft-versus-host disease (GvHD) (5). The CsA-AI model is being studied for three reasons. Firstly, the animal model, and in particular the chronic phase of the disease, has been reported to have several macroscopic and histopathologic similarities with human scleroderma (6,7). Secondly, CsA-AI is clinically and experimentally examined for its graft- versus-tumour potential against lympho-hematopoietic malignancies as well as metastatic breast cancer (8). And thirdly, CsA-AI has been very informative in terms of T cell development and tolerance induction, including central as well as peripheral control of autoreactivity (9, 10). In the present review, a summary of the characteristics of CsA-AI will be given. Next, the supposed mechanism of CsA for interference with central tolerance induction will be presented. Finally, the role of peripheral tolerance, and in particular dominant T cell tolerance as mediated by regulatory T cells, will be discussed in relation to induction of CsA-AI as well as to strain-related resistance to CsA-AI.

scholarly journals Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2920-2928 ◽  
Author(s):  
DS Snyder ◽  
NJ Chao ◽  
MD Amylon ◽  
J Taguchi ◽  
GD Long ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Graft Versus Host ◽  
Acute Myelogenous ◽  
Total Body ◽  
First Complete Remission

Abstract Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation > 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.

scholarly journals Prevention of Graft-Versus-Host Disease in Mice Using a Suicide Gene Expressed in T Lymphocytes

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4636-4645 ◽  
Author(s):  
José L. Cohen ◽  
Olivier Boyer ◽  
Benoı̂t Salomon ◽  
Rosine Onclercq ◽  
Frédéric Charlotte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Therapeutic Strategy ◽  
Suicide Gene ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Cell Pool ◽  
Ganciclovir Treatment

Abstract Alloreactive T cells present in a bone marrow transplant are responsible for graft-versus-host disease (GVHD), but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells, while preserving a competent T-cell pool of donor origin. We generated transgenic mice expressing in their T lymphocytes the Herpes simplex type 1 thymidine kinase (TK) suicide gene that allows the destruction of dividing T cells by a ganciclovir treatment. T cells expressing the TK transgene were used to generate GVHD in irradiated bone marrow grafted mice. We show that a short 7-day ganciclovir treatment, initiated at the time of bone marrow transplantation, efficiently prevented GVHD in mice receiving TK-expressing T cells. These mice were healthy and had a normal survival. They maintained a T-cell pool of donor origin that responded normally to in vitro stimulation with mitogens or third party alloantigens, but were tolerant to recipient alloantigens. Our experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T cells.

Sign in / Sign up

Export Citation Format

Share Document