scholarly journals Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yi-Bin Chen ◽  
Tatsuo Kawai ◽  
Thomas R. Spitzer
Keyword(s):  
Bone Marrow ◽  
Kidney Transplantation ◽  
Bone Marrow Transplantation ◽  
Organ Transplantation ◽  
Marrow Transplantation ◽  
Mixed Chimerism ◽  
Clonal Deletion ◽  
Primate Model ◽  
Hematopoietic Chimerism ◽  
Specific Tolerance

The induction of specific tolerance, in order to avoid the detrimental effects of lifelong systemic immunosuppressive therapy after organ transplantation, has been considered the “Holy Grail” of transplantation. Experimentally, tolerance has been achieved through clonal deletion, through costimulatory blockade, through the induction or infusion of regulatory T-cells, and through the establishment of hematopoietic chimerism following donor bone marrow transplantation. The focus of this review is how tolerance has been achieved following combined bone marrow and kidney transplantation. Preclinical models of combined bone marrow and kidney transplantation have shown that tolerance can be achieved through either transient or sustained hematopoietic chimerism. Combined transplants for patients with multiple myeloma have shown that organ tolerance and prolonged disease remissions can be accomplished with such an approach. Similarly, multiple clinical strategies for achieving tolerance in patients without an underlying malignancy have been described, in the context of either transient or durable mixed chimerism or sustained full donor hematopoiesis. To expand the chimerism approach to deceased donor transplants, a delayed tolerance approach, which will involve organ transplantation with conventional immunosuppression followed months later by bone marrow transplantation, has been successful in a primate model. As combined bone marrow and organ transplantation become safer and increasingly successful, the achievement of specific tolerance may become more widely applicable.

scholarly journals A Review of Cyclophosphamide-Induced Transplantation Tolerance in Mice and Its Relationship With the HLA-Haploidentical Bone Marrow Transplantation/Post-Transplantation Cyclophosphamide Platform

2021 ◽  
Vol 12 ◽  
Author(s):  
Hisanori Mayumi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Bone Marrow Cells ◽  
Mixed Chimerism ◽  
Post Transplantation ◽  
Clonal Deletion ◽  
Marrow Graft ◽  
Induced Tolerance

The bone marrow transplantation (BMT) between haplo-identical combinations (haploBMT) could cause unacceptable bone marrow graft rejection and graft-versus-host disease (GVHD). To cross such barriers, Johns Hopkins platform consisting of haploBMT followed by post-transplantation (PT) cyclophosphamide (Cy) has been used. Although the central mechanism of the Johns Hopkins regimen is Cy-induced tolerance with bone marrow cells (BMC) followed by Cy on days 3 and 4, the mechanisms of Cy-induced tolerance may not be well understood. Here, I review our studies in pursuing skin-tolerance from minor histocompatibility (H) antigen disparity to xenogeneic antigen disparity through fully allogeneic antigen disparity. To overcome fully allogeneic antigen barriers or xenogeneic barriers for skin grafting, pretreatment of the recipients with monoclonal antibodies (mAb) against T cells before cell injection was required. In the cells-followed-by-Cy system providing successful skin tolerance, five mechanisms were identified using the correlation between super-antigens and T-cell receptor (TCR) Vβ segments mainly in the H-2-identical murine combinations. Those consist of: 1) clonal destruction of antigen-stimulated-thus-proliferating mature T cells with Cy; 2) peripheral clonal deletion associated with immediate peripheral chimerism; 3) intrathymic clonal deletion associated with intrathymic chimerism; 4) delayed generation of suppressor T (Ts) cells; and 5) delayed generation of clonal anergy. These five mechanisms are insufficient to induce tolerance when the donor-recipient combinations are disparate in MHC antigens plus minor H antigens as is seen in haploBMT. Clonal destruction is incomplete when the antigenic disparity is too strong to establish intrathymic mixed chimerism. Although this incomplete clonal destruction leaves the less-proliferative, antigen-stimulated T cells behind, these cells may confer graft-versus-leukemia (GVL) effects after haploBMT/PTCy.

CD26 Inhibition Enhances Allogeneic Donor Cell Homing and Engraftment after In Utero Bone Marrow Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1275-1275
Author(s):  
William H. Peranteau ◽  
Masayuki Endo ◽  
Obinna O. Adibe ◽  
Aziz Merchant ◽  
Philip Zoltick ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Donor Cell ◽  
In Utero ◽  
Cell Homing ◽  
Time Points ◽  
Hematopoietic Chimerism ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract In utero bone marrow transplantation (IUBMT) induces donor-specific tolerance for postnatal cellular or organ transplantation. Consistent induction of tolerance requires a threshold of mixed hematopoietic chimerism (>1%). CD26 is a peptidase whose inhibition has been demonstrated to influence granulocyte colony-stimulating factor induced mobilization of hematopoietic stem cells and increase homing and engraftment of BM cells in adult transplantation models. We hypothesized that CD26 inhibition would increase the frequency and levels of allogeneic hematopoietic chimerism after IUBMT. Methods: B6 GFP BM was injected intravenously into E14 Balb/c fetal mice at a dose of 20e6 cells/fetus with or without CD26 inhibition with diprotin A. Early kinetic analysis was performed to assess donor cell homing to fetal liver (FL). Peripheral blood (PB) was analyzed up to 20 weeks after birth for donor cell chimerism and multilineage engraftment by flow cytometry. PB was also analyzed for donor cell chimerism at the same time points from Balb/c mice receiving 10e6 CD26 inhibited GFP BM cells coinjected with 10e6 noninhibited congenic B6Ly5.2 BM cells at E14 to assess for an in utero competitive advantage provided by CD26 inhibition. Results: CD26 inhibition increased donor cell homing to the FL at 24, 48 and 96 hours after injection (69.27±8.19 vs 30.21±6.44, 57.20±14.63 vs 36.80±14.20, 46.14±15.79 vs 12.09±7.01; p<0.05 at all time points). The frequency and levels of engraftment at 4 weeks of life were increased in those mice receiving CD26 inhibited BM compared to noninhibited BM (50.0% vs 22.5%; 20.48±14 vs 6.96±8.44, p<0.05). Chimerism was multilineage and maintained at 20 weeks of age (figure 1a) supporting improvement of engraftment at the stem or early progenitor cell level (* p<0.05 comparing chimerism levels between inhibitied and noninhibited cells). The coinjection of CD26 inhibited and noninhibited cells resulted in higher levels of engraftment of inhibited cells at all time points up to 16 weeks of age arguing for a competitive engraftment advantage of early progenitor cells provided by CD26 inhibition (figure 1b). Conclusion: CD26 inhibition of donor BM prior to IUBMT results in an increased efficiency of donor engraftment and higher levels of chimerism. CD26 inhibition offers a potential mechanism to increase the level of engraftment and the rate of donor specific tolerance and may facilitate combined pre and postnatal strategies for cellular and organ transplantation. Figure Figure

scholarly journals Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen.

1989 ◽  
Vol 169 (2) ◽  
pp. 493-502 ◽  
Author(s):  
Y Sharabi ◽  
D H Sachs
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Host Resistance ◽  
Marrow Transplantation ◽  
Whole Body ◽  
Mixed Chimerism ◽  
Skin Grafts ◽  
Preparative Regimen ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia.

Effects of mixed hematopoietic chimerism in a mouse model of bone marrow transplantation for sickle cell anemia

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3960-3965 ◽  
Author(s):  
Robert Iannone ◽  
Leo Luznik ◽  
Laura W. Engstrom ◽  
Sherrie L. Tennessee ◽  
Frederic B. Askin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Mouse Model ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Marrow Transplantation ◽  
Mixed Chimerism ◽  
Normal Donor ◽  
Hematopoietic Chimerism ◽  
Allogeneic Marrow

Sickle cell anemia (SCA) is an inherited disorder of β-globin, resulting in red blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expectancy. Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated with an 8% to 10% mortality rate, primarily from complications of marrow-ablative conditioning. Transplantation of allogeneic marrow after less intensive conditioning reduces toxicity but may result in stable mixed hematopoietic chimerism. The few SCA patients who inadvertently developed mixed chimerism after BMT remain symptom free, suggesting that mixed chimerism can reduce disease-related morbidity. However, because the effects of various levels of mixed chimerism on organ pathology have not been characterized, this study examined the histologic effects of an increasing percentage of normal donor hematopoiesis in a mouse model of BMT for SCA. In lethally irradiated normal mice that were reconstituted with varying ratios of T-cell–depleted marrow from normal and transgenic “sickle cell” mice, normal myeloid chimerism in excess of 25% was associated with more than 90% normal hemoglobin (Hb). However, 70% normal myeloid chimerism was required to reverse the anemia. Organ pathology, including liver infarction, was present in mice with sickle Hb (HbS) levels as low as 16.8% (19.6% normal myeloid chimerism). Histologic abnormalities increased in severity up to 80% HbS, but were less severe in mice with more than 80% HbS than in those with 40% to 80% HbS. Therefore, stable mixed chimerism resulting from nonmyeloablative BMT may reduce the morbidity from SCA, but prevention of all disease complications may require minimizing the fraction of circulating sickle red cells.

Donor Specific Unresponsiveness Develops Following Loss of Chimerism in Recipients of Haploidentical Combined Bone Marrow/Kidney Transplantation but Not in Recipients of Bone Marrow Transplant Alone.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3103-3103
Author(s):  
Giovanna Andreola ◽  
Juanita Shaffer ◽  
A. Benedict Cosimi ◽  
Tatsuo Kawai ◽  
Pete Cotter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Failure ◽  
Kidney Transplantation ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Renal Allograft ◽  
Mixed Chimerism ◽  
Bone Marrow Transplants ◽  
Myeloablative Conditioning

Abstract Pre-clinical data in monkeys receiving non-myeloablative conditioning followed by MHC-mismatched kidney and bone marrow transplantation show that transient chimerism is sufficient to permit achievement of long-term tolerance to a simultaneous donor renal allograft. Our group has recently reported successful induction of tolerance to donor kidneys in patients with advanced multiple myeloma and renal failure through combined bone marrow and kidney transplantation in the HLA-identical setting. On the basis of these results, five end-stage renal failure patients without malignant disease received simultaneous kidney and bone marrow transplantation from haploidentical HLA mismatched related donor after non-myeloablative conditioning with MEDI-507 (anti-CD2 humanized mAb; MedImmune), cyclophosphamide, thymic irradiation and peritransplant cyclosporine. Transplantation of kidney and bone marrow were both performed on Day 0. All patients developed initial mixed chimerism but lost their chimerism by Day 21. We have analyzed three patients who successfully discontinued immunosuppression on Days +240, +422 and +244. At a follow-up of 47, 38, and 17 months, all three patients are off immunosuppression without allograft rejection. T-cell counts exceeded 100 cells/μL by Day +128, +21, +21, respectively, and a high early prevalence of CD4+CD25high cells was detected. Post-transplant in vitro alloreactivity assays (bulk MLR/CML) showed the development of long-lasting donor-specific unresponsiveness in all three patients. In patients in whom renal tubular epithelial cells (RTEC) were cultured from the donor kidney, no killing of donor RTEC was detected post-transplant. We also assessed alloresponses in chemorefractory lymphoma patients receiving haploidentical bone marrow transplantation with a similar conditioning regimen. In contrast to the recipients of combined kidney/bone marrow transplants, these patients showed sustained global hyporesponsiveness in CML and MLR. However, loss of donor chimerism was associated with the eventual appearance of measurable anti-donor CML and/or MLR responses. In contrast, donor-specific and host-specific unresponsiveness with strong anti-3rd party responses developed in a sustained mixed chimera who received haploidentical stem cell transplantation with a modification of this conditioning protocol (i.e. different dose of MEDI-507, Isolex-selected CD34+ cells from G-CSF mobilized PBMC and the addition of fludarabine). In summary, we have obtained proof of principle that durable multilineage mixed chimerism with donor- and host-specific tolerance can be achieved without GVHD in humans receiving haploidentical HCT. In recipients of combined kidney/bone marrow transplants but not in recipients of bone marrow alone, patients who lose chimerism develop donor-specific unresponsiveness. These studies point to a role for the renal allograft in maintaining long-term tolerance following loss of initial donor chimerism.

Suboptimal Busulphan Exposure Is Associated with Mixed Hematopoietic Chimerism, a Risk Factor for Rejection in Bone Marrow Transplantation for Homozygous beta Thalassemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1149-1149 ◽  
Author(s):  
J. David Dennison ◽  
Shoaib Al Zadjali ◽  
Melanie Tauro ◽  
Salam Al Kindi ◽  
S. Muralitharan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Class Ii ◽  
Mixed Chimerism ◽  
Beta Thalassemia ◽  
Transplant Outcome ◽  
Number Of Patients ◽  
Hematopoietic Chimerism

Abstract Bone marrow transplantation is the only curative treatment modality available for patients with homozygous beta thalassemia. Although the transplant outcome for good-risk patients is uniformly excellent, rejection continues to remain a serious complication with reported incidences ranging from 10–40%. Since mixed hematopoietic chimerism (MC) has been shown to be a risk factor for rejection in homozygous beta thalassemia, we investigated the relationship between MC and busulfan pharmacokinetics (Bu PK). Between May 1999 and April 2004, we retrospectively analyzed 24 consecutive patients with homozygous beta thalassemia transplanted in this center, for whom data on Bu PK was available. The median age was 9.5yr (3–15 yr). Sixteen (67%) patients were Class II, six (25%) Class III, one patient (4%) Class I and one patient (4%) Class II or III as per the Lucarelli classification for transplant outcome. The conditioning regimen consisted of busulfan/cyclophosphamide in 21/24 (88%) and busulfan/cyclophosphamide/ATG in 3/24 (12%) patients. All patients received a standard dose of cyclophosphamide (200mg/kg) but had varying doses of busulfan, ranging from 15 to 29mg/kg (mean 21mg/kg). Nine out of the 24 patients (38%) received the intravenous preparation of busulfan. Cyclosporine and short-course methotrexate were used as graft versus host disease (GVHD) prophylaxis. Bu PK was performed by liquid chromatography mass-spectrometry on frozen plasma samples obtained after doses 1, 5 and 13. Chimerism was assessed after BMT by DNA fingerprinting using a panel of informative markers. Acute GVHD was seen in 13/23 (56%) evaluable patients, 9/13 were grade I & II and 3/13 grade III & IV. Veno-occlusive disease of the liver (VOD) as per the Seattle and Baltimore criteria occurred in 14/24 (58%) and 3/24 (12%) respectively. MC was documented in 5/24 (21%) patients while graft rejection occurred in 2/23 (9%) evaluable patients. Non-rejection mortality was 4% (1/24). Thalassemia-free survival was 88% (21/24) with a median follow up of 31 months. MC significantly predicted for rejection (p=0.04). Analysis of Bu PK showed that patients with MC had significantly lower minimum and steady state busulfan concentrations (Cmin and Css) and faster clearance of the drug (CL/F) when compared to patients with complete chimerism. REJECTION [n=2] NO REJECTION [n=21] MIXED CHIMERISM 2 [100%] 3 [14%] p = 0.04 MIXED CHIMERISM [n=5] COMPLETE CHIMERISM [n=19] Dose 1 Bu PK Cmin (ng/ml) 201.00±44.21 298.16±98.08 p < 0.05 Css (ng/ml) 616.2±108.4 842.83±252.2 p < 0.05 Cl/F (L/h/kg) 0.343±0.087 0.260±0.058 p < 0.05 Mean Bu PK Cmin (ng/ml) 207.6±48.3 288.4±86.3 p < 0.05 Cl/F (L/h/kg) 0.345±0.091 0.289±0.045 p < 0.05 Although the number of patients is small, this study confirms MC to be a risk factor for rejection, and further demonstrates the occurrence of MC post BMT to be associated with low busulfan systemic exposure during conditioning. Individualizing busulfan dosage based on Bu PK may therefore be one strategy to minimize rejection in bone marrow transplantation for homozygous thalassemia.

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