scholarly journals Impact of pretransplant conditioning and donor T cells on chimerism, graft-versus-host disease, graft-versus-leukemia reactivity, and tolerance after bone marrow transplantation

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2515-2523
Author(s):  
RL Truitt ◽  
AA Atasoylu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Mixed Chimerism ◽  
Cell Content ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Graft rejection, mixed chimerism, graft-versus-host disease (GVHD), leukemia relapse, and tolerance are interrelated manifestations of immunologic reactivity between donor and host cells that significantly affect survival after allogeneic bone marrow transplantation (BMT). In this report, a mouse model of BMT, in which the donor and host were compatible at the major histocompatibility complex (MHC), was used (1) to examine the interrelationship of pretransplant conditioning and T- cell content of donor BM with regard to lymphoid chimerism and GVHD and (2) to determine how these factors affected graft-versus-leukemia (GVL) reactivity and donor-host-tolerance. AKR (H-2k) host mice were administered optimal or suboptimal total body irradiation (TBI) as pretransplant conditioning followed by administration of BM cells from B10.BR (H-2k) donor mice with or without added spleen cells as a source of T lymphocytes. Transplanted mice were injected with a supralethal dose of AKR leukemia cells 20 and 45 days post-BMT to assess GVL reactivity in vivo. The pretransplant conditioning of the host and T- cell content of the donor marrow affected the extent of donor T-cell chimerism and the severity of GVH disease. GVL reactivity was dependent on transplantation of mature donor T cells and occurred only in complete chimeras. Transplantation of T-cell-deficient BM resulted in the persistence of host T cells, ie, incomplete donor T-cell chimerism, even when lethal TBI was used. Mixed chimerism was associated with a lack of GVL reactivity, despite the fact that similar numbers of donor T cells were present in the spleens of mixed and complete chimeras. In this model, moderate numbers of donor T cells facilitated complete donor T-cell engraftment, caused only mild GVHD, and provided a significant GVL effect without preventing the subsequent development of tolerance after conditioning with suboptimal TBI. In contrast, severe, often lethal, GVHD developed when the dose of TBI was increased, whereas tolerance and no GVH/GVL reactivity developed when the T-cell content of the marrow was decreased.

scholarly journals Impact of pretransplant conditioning and donor T cells on chimerism, graft-versus-host disease, graft-versus-leukemia reactivity, and tolerance after bone marrow transplantation

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2515-2523 ◽  
Author(s):  
RL Truitt ◽  
AA Atasoylu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Mixed Chimerism ◽  
Cell Content ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Abstract Graft rejection, mixed chimerism, graft-versus-host disease (GVHD), leukemia relapse, and tolerance are interrelated manifestations of immunologic reactivity between donor and host cells that significantly affect survival after allogeneic bone marrow transplantation (BMT). In this report, a mouse model of BMT, in which the donor and host were compatible at the major histocompatibility complex (MHC), was used (1) to examine the interrelationship of pretransplant conditioning and T- cell content of donor BM with regard to lymphoid chimerism and GVHD and (2) to determine how these factors affected graft-versus-leukemia (GVL) reactivity and donor-host-tolerance. AKR (H-2k) host mice were administered optimal or suboptimal total body irradiation (TBI) as pretransplant conditioning followed by administration of BM cells from B10.BR (H-2k) donor mice with or without added spleen cells as a source of T lymphocytes. Transplanted mice were injected with a supralethal dose of AKR leukemia cells 20 and 45 days post-BMT to assess GVL reactivity in vivo. The pretransplant conditioning of the host and T- cell content of the donor marrow affected the extent of donor T-cell chimerism and the severity of GVH disease. GVL reactivity was dependent on transplantation of mature donor T cells and occurred only in complete chimeras. Transplantation of T-cell-deficient BM resulted in the persistence of host T cells, ie, incomplete donor T-cell chimerism, even when lethal TBI was used. Mixed chimerism was associated with a lack of GVL reactivity, despite the fact that similar numbers of donor T cells were present in the spleens of mixed and complete chimeras. In this model, moderate numbers of donor T cells facilitated complete donor T-cell engraftment, caused only mild GVHD, and provided a significant GVL effect without preventing the subsequent development of tolerance after conditioning with suboptimal TBI. In contrast, severe, often lethal, GVHD developed when the dose of TBI was increased, whereas tolerance and no GVH/GVL reactivity developed when the T-cell content of the marrow was decreased.

scholarly journals A New Cellular Immunotherapy for the Treatment of Multiple Myeloma without Development of Graft-Versus-Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3339-3339
Author(s):  
Michael A Firer ◽  
Sofi Yado ◽  
Luboshits Galia ◽  
Reuven Or
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Term Survival ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers. Despite recent advances, long-term survival is rare after autologous bone marrow transplantation (auto-BMT) and/or treatment with recently introduced anti-myeloma agents and disease recurs in virtually all patients. Allogeneic bone marrow transplantation (allo-BMT) is an effective treatment that can provide partial or complete remission in patients with MM. The therapeutic potential of allo-BMT is attributed to the "graft-versus-myeloma" (GvM) effect that aims to destroy residual tumor cells that survived an induction protocol of chemotherapy/radiotherapy and to maintain immune surveillance to prevent relapse. However, allo-BMT remains a controversial treatment, since the donor T cells that mediate the GvM effect are also the source of the cells that react to other tissue alloantigens and induce graft versus-host disease (GvHD), a major cause of morbidity and mortality in allo-BMT recipients. Nonetheless, allo-BMT remains the only potentially curable treatment for MM. Recently TCR Vβ CDR3-size spectratype analyses in an animal model of MM identified T cells subfamilies involved in the anti-host and anti-tumor reactivity. We have now carried this work further and tested the potential of integrating auto-BMT with a donor lymphocyte infusion (DLI) composed only of anti-MM reactive Vβ 2, 3 and 8.3 T cell subfamilies. The results demonstrate that these T cell subsets are indeed involved in the generation of a potent GvM response in MM bearing mice and is associated with enhanced survival. Importantly, the GvM response was not accompanied by the development of GvHD. Nonetheless, the GvM response was not sufficient to completely inhibit relapse. We then pre-stimulated donor T cells with MM cells in vitro in the presence of co-stimulatory factors and found that our selective DLI protocol induced a vigorous and long-lasting GvM which translated into long-term survival, again in the complete absence of GvHD. Interestingly, quite similar results were obtained by treating MM-bearing mice with repeat doses of naïve donor Vβ 2, 3 and 8.3 T cell subfamilies. The treated mice showed significantly lower serum paraprotein levels and myeloma infiltration in bone marrow and spleen. Taken together, the results suggest that a transplantation protocol involving only tumor cell-reactive donor T cell subfamilies might be devised for MM patients that results in a potent GvM with enhanced survival but without symptoms of GvHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Patient Bone Marrow Chimerism at Time of Donor Lymphocyte Infusion Predicts Development of Graft Versus Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2132-2132
Author(s):  
Eva AS Koster ◽  
Liesbeth C. de Wreede ◽  
Sylwia Wallet-Malicka ◽  
Lisette Bogers ◽  
Peter van Balen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Hazard Ratio ◽  
The State ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Donor Type

Abstract After allogeneic stem cell transplantation (alloSCT), donor T cells targeting patient derived hematopoietic cells can induce a Graft versus Leukemia (GvL) effect preventing relapse. However, targeting of healthy patient tissues can cause Graft versus Host Disease (GvHD). The inflammatory environment induced by pre transplantation conditioning, the number of donor T cells in the graft, genetic disparity between patient and donor and the presentation of allo-antigens by activated patient derived antigen-presenting cells (APC) to donor T cells play a role in the development of GvL and/or GvHD. Donor T cell depletion (TCD) reduces GvHD and GvL. After TCD alloSCT, postponed prophylactic donor lymphocyte infusions (pDLI) are often needed to induce a GvL effect. When using 10/10 matched donors, our first dose of pDLI at six months after TCD alloSCT contained 3.0x10^6 T cells/kg (related donor, RD) or 1.5x10^6 T cells/kg (unrelated donor, UD). We evaluated whether the risk of developing GvHD after DLI is influenced by the donor type, intensity of the conditioning and/or patient bone marrow (BM) chimerism at time of DLI Sixty patients with acute leukemia (52 AML, 8 ALL; median age 57; 27 RD, 33 UD) received pDLI at a median of 6.4 months after TCD alloSCT in the absence of GVHD or relapse. Twenty-four patients received myeloablative (MA) conditioning consisting of cyclophosphamide and TBI. 36 patients received non-myeloablative (NMA) conditioning based on fludarabin and busulphan. TCD was performed by adding 20mg alemtuzumab to the graft. Only MA conditioned patients with an UD (n=12) received post transplantation ciclosporin as GvHD prophylaxis, which was tapered from 1 month after alloSCT. Clinically significant GvHD was defined as need of therapeutic systemic immunosuppression (tIS) for GvHD for at least 2 weeks or until death. Bone Marrow (BM) chimerism was measured prior to DLI. Three categories of patient chimerism levels were defined: no patient derived cells (absent), patient derived cells present, but < 5% (low), or ≥ 5% (high). In case of persisting or increasing patient chimerim after pDLI, a second DLI was given at 3-6 months after the first. A multi-state model was designed (Figure 1) with the first DLI (DLI1) as starting state and time. Patients starting tIS after DLI1 transit to the state tIS. Patients who need a second DLI, develop a relapse or die, transit to these respective states. Patients who stay in the state of DLI1 are considered to have a positive outcome. All patients had a follow-up of at least one year after DLI. Numbers in the boxes in Figure 1 represent the number of patients in that state at 1 year after DLI1 and numbers next to the arrows indicate the numbers of patients who made the transition between the two states. Donor type (unrelated versus related), conditioning (NMA versus MA) and patient BM chimerism at time of DLI were included in a Cox model for the transition hazards to investigate their association with the development of GvHD after DLI. For the total group, the cumulative incidence of tIS at 1 year after pDLI was 33% (95% CI 21-45%). Patients with an UD had a hazard ratio (HR) of 1.1 (95% CI 0.4-3.3) of needing tIS after DLI1 compared to patients with a RD. Compared to MA conditioning, NMA conditioned patients had a hazard ratio of 2.1 (95% CI 0.5-8.9) of needing tIS after DLI. They had a HR of 0.2 (95% CI 0.04-0.95) of stopping tIS compared to MA conditioned patients, indicating that DLI after NMA conditioning is associated with more severe GVHD. We hypothesized that this was due to the persistence of patient derived APC. BM chimerism at time of DLI was measured in 47 patients. After NMA and MA conditioning, BM patient chimerism was absent in 14% and 56%, low in 41% and 39%, and high in 45% and 6%, respectively (Fisher's exact test p=0.002 for difference between type of conditioning). Compared to the group without patient chimerism, the low and high patient chimerism group had a HR of 1.9 (95% CI 0.9-4.2) and 3.6 (95% CI 1.7-8.0) of needing tIS after DLI, respectively (Figure 2), demonstrating that the level of patient chimerism is a strong predictor for development of GvHD after DLI, even when taking into account the type of conditioning regimen. Patient BM chimerism at time of pDLI is a strong and independent predictor for the risk of developing GvHD. Dose reduction in case of an UD equalized the GvHD risk compared to a RD. When choosing a T cell dose for pDLI, patient chimerism should be considered a relevant parameter. Disclosures No relevant conflicts of interest to declare.

scholarly journals Thymus Transplantation Plus Allogeneic Bone Marrow Transplantation Can Induce Strong Graft-Versus Leukemia Effects with Low Risk of Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5798-5798
Author(s):  
Yuming Zhang ◽  
Xiaoqing Feng ◽  
Cuiling Wu ◽  
Wenling Guo ◽  
Huiping Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Cd4 Cells ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Thymus Transplantation

Abstract Abstract: [Objective] Allogeneic bone marrow transplantation (allo-BMT) has been used for the treatment of refractory leukemia and donor lymphocyte infusion (DLI) was used for the purpose of graft versus leukemia (GVL) effects. However, DLI is associated with a risk of graft versus host disease (GVHD). Thus, new cellular-based methods are desired. In the present study, we performed thymus transplantation (TT) plus allo-BMT to explore it’s anti leukemia effects. [Methods] Recipient B6 mice (H-2b) bearing leukemia (EL-4 cells, H-2b) were irradiated 8 Gy. The next day, bone marrow cells from BALB/c mice (H-2d) were transplanted into the B6 mice. Simultaneously, DLI and thymus transplantation from the same donor were carried out. The survival period of the recipient B6 mice were examined, histological studies were performed in the liver, intestine, and the engrafted thymus from the recipients 4 weeks after the BMT. Surface markers on lymphocytes from the spleen were analyzed by 3-color fluorescence staining using a FACScan system to determine chimerism. [Results]. All mice treated with BMT showed fully donor-derived chimerism(H-2d). The survival rate in mice treated with BMT plus TT was significantly prolonged compared with those treated with BMT alone or BMT plus DLI. Histologically, both the cortex and medullar areas of the engrafted thymus under the renal capsule were clearly shown. Normal T-cell differentiation was also observed in the engrafted thymus. Microscopic founding of small intestine and liver in the BMT plus TT group indicated mild GVHD, whereas those treated with BMT plus DLI showed moderated to serious GVHD. The number of the CD4+ cells was significantly greater in the mice treated with BMT+TT compared with those with BMT alone or those with BMT + DLI. The percentage of FoxP3+ regulatory T cells among CD4+ cells was higher in the mice treated with BMT + TT comparable to those treated with BMT + DLI. The results for CD8+ T cells were similar to those for CD4+ cells. [Conclusion]. Allo-BMT combined with TT induces high thymopoiesis, and can elicit strong GVL effects with mild GVHD reaction. We thus found that donor-derived T cells play an important role in the treatment of leukemia. Also the details of the mechanisms are still unknown, one possibilities may be the continuous supplementation of T cells from the allogeneic thymus. The results of the present study suggest this strategy will become a new way for the treatment of refractory or relapse leukemia in human. Disclosures No relevant conflicts of interest to declare.

Bone Marrow T Cells Are More Effective Than Peripheral T Cells in Inducing Chimeric Conversion Following MHC-Mismatched Nonmyeloablative Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4593-4593
Author(s):  
Seok-Goo Cho ◽  
Hyunsil Park ◽  
Min Jung Park ◽  
Ho-Youn Kim ◽  
Jong-Wook Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Memory T Cells ◽  
Mixed Chimerism ◽  
Graft Versus Host ◽  
Peripheral T Cells ◽  
Mixed Chimeras

Abstract Background & Objectives: Recently, T cells in BM have attracted renewed interest because they are now known to have different surface phenotypes, subsets, and activation states from those in the periphery. Memory T cells undergo extensive migration from the blood to the BM and vice versa. The BM plays an important role in preferential homing and extensive proliferation of memory T cells, and contributes considerably to the longlived memory T cell pool. BM T cells are more activated than their splenic counterparts and have a higher rate of local proliferation. Although BM-T (NK1.1– CD4+ or CD8+) cells did not induce lethal GVH disease, even at high cell numbers, BM-T cells mediated vigorous graft-versus-tumor activity and facilitated engraftment of hematopoietic progenitor cells. These studies suggested that BM-T cells could be a useful cellular source for adoptive immunotherapy following ABMT, instead of peripheral T cells. Non-myeloablative bone marrow transplantation (NMT) and allogeneic mixed chimerism can provide an environment adequate for diminishing susceptibility to DLI-mediated GVHD and an immunological platform for DLI in both mouse and human models. In patients treated with DLI, a successful GVL effect is often associated with conversion to complete donor chimerism, supporting the concept of a graft-versus-host (GVH) response as part of the GVL effect. Thus, a quiet chimeric conversion following DLI is desirable to reach an optimal DLI-mediated GVL effect, without the occurrence of GVHD. Although in a mouse model, the administration of non-tolerant donor spleen cells to established mixed chimeras has been shown to convert mixed hematopoietic chimerism to full donor chimerism, without the concomitant development of GVHD, DLI in humans frequently results in serious GVHD and life-threatening complications. However, the use of BM-T cells, as compared with spleen T cells (SP-T), as the DLI source has not been investigated in allogeneic mixed chimerism prepared with NMT. In this study, we evaluated the beneficial alloreactivity of DLI using cryopreserved BM-T cells, a by-product obtained during the T cell depletion (TCD) procedure in BM grafting, to effectively induce chimeric conversion without the occurrence of GVHD in MHC-mismatched NMT. Methods: Cells were prepared using established procedures. During the T cell depletion (TCD) procedure in BM grafting, BM-T cells were obtained as a by-product and then cryopreserved for subsequent DLI using BM-T cells 21 days after the bone marrow transplant. Results: The administration of 5–10 × 105 BM-T (Thy1.2+) cells in mixed chimeras resulted in complete chimeric conversion, with self-limited graft-versus-host disease (GVHD) and no pathological changes. However, the administration of 5–10 × 105 SP-T (Thy1.2+) cells resulted in persistent mixed chimerism, with pathological GVHD signs in the liver and intestine. Conclusion: Our results suggest that DLI using BM-T cells, even in small numbers, could be more potent for inducing chimeric conversion in mixed chimerism than DLI using SP-T cells. Further study is needed to determine whether cryopreserved BM-T cells are an effective cell source for DLI to consolidate donor-dominant chimerism in clinical practice, without concerns about GVHD.

scholarly journals Extended-cycle elutriation to adjust T-cell content in HLA-disparate bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 307-317 ◽  
Author(s):  
RR Quinones ◽  
RH Gutierrez ◽  
PA Dinndorf ◽  
RE Gress ◽  
AB Ney ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Lymphocytic Leukemia ◽  
Mixed Chimerism ◽  
Cell Content

We report the development of a double-cycle elutriation (DCE) technique separating 3 or greater logs of T cells from a stem-cell-enriched marrow fraction and the results of phase I T-cell depletion studies with HLA-disparate related bone marrow transplantation (BMT) donors in two patient groups. In group 1, 10 patients with refractory hematopoietic malignancies received combination chemotherapy, total body irradiation (TBI), and immunosuppression (pre- and post-BMT), and hematopoietic rescue with a marrow transplant, depleted of T cells by elutriation. Potentially to promote engraftment and a graft-versus- leukemia (GVL) effect, 0.5 to 0.75 x 10(5) T cells/kg were added back. All 10 patients engrafted. Five patients developed acute graft-versus- host disease (GVHD; four grade II, one grade III) and two subsequently developed chronic GVHD. Two patients have relapsed (median follow-up, 206 days; range, 46 to 1,035). Four patients died of BMT-related complications (three of infection, one of veno-occlusive disease [VOD]). Four patient are disease-free survivors (median follow-up, 960 days; range, 670 to 1,035). Group 2 included five infants, four with congenital lymphohematopoietic deficiencies and one with refractory acute lymphocytic leukemia (ALL). In these infants, busulfan and increased cyclophosphamide were substituted for TBI. Only the ALL patient received added T cells. Three patients engrafted: one has stable mixed chimerism, one relapsed with ALL, and one rejected the marrow. One patient had primary autologous recovery, while another failed to engraft. None developed GVHD. We conclude that, in this setting of HLA-disparate BMT with post-BMT antithymocyte globulin (ATG) and corticosteroids, DCE significantly depletes T cells from the marrow and that a defined number of T cells can be added without the occurrence of severe GVHD.

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