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Mixed Chimerism (mixed + chimerism)

Distribution by Scientific Domains
Medical Sciences100%
Distribution within Medical Sciences
Transplantation50%
Hematology25%

Selected Abstracts

Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010
N. Pilat
Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-, induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach. [source]

The Role of Non-Deletional Tolerance Mechanisms in a Murine Model of Mixed Chimerism with Costimulation Blockade

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005
Sinda Bigenzahn
Peripheral and central clonal deletion are important tolerance mechanisms in models using bone marrow transplantation (BMT) with costimulation blockade (CB). However, since tolerance can be found before peripheral deletion is complete and since elimination of recipient CD4+ cells at the time of BMT prevents tolerance induction, we investigated the potential roles of regulation and anergy in such a murine model. We found that transient elimination of CD25+ cells or neutralization of IL2 immediately after BMT and CB prevented the induction of skin graft tolerance. Cotransfer into SCID mice of CD4+ cells taken from chimeras early after BMT, together with naďve recipient-type CD4+ cells significantly prolonged donor skin graft survival. In contrast, cotransfer of CD4+ cells harvested from chimeras late after BMT did not prolong donor skin graft survival. Besides, depletion of CD25+ cells in established chimeras several months post-BMT did not break tolerance. In vivo administration of recombinant IL2 inhibited chimerism and tolerance neither early nor late post-BMT, arguing against a decisive role for classical anergy. Thus, CD4 cell-mediated regulation contributes significantly to tolerance induction early after BMT, but appears to have no critical role in the maintenance of tolerance. [source]

Analysis of chimerism during the early period after allogeneic peripheral stem cell transplantation

INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 6 2001
B. Gleissner
As there are few reports on early evaluation of chimerism, we assessed fluorescence short tandem repeats (STR) by polymerase chain reaction (PCR) assays to analyse donor and recipient characteristics at early time points after peripheral stem cell transplantation (PBSCT). Peripheral blood of 13 patients was analysed in 1- to 2-day intervals starting from the day of PBSCT. Donor and recipient allelic patterns were determined by a commercially available multiplex STR assay that simultaneously evaluates four or five gene loci. Mixed chimerism appeared in all patients during days 1,9 after transplantation and preceded haematologic engraftment for 3,12 days. Even patients without myeloablative conditioning therapy (n=4) revealed donor allelic patterns within 1,5 days. Nine patients changed during the following days to a complete donor allelic pattern and had an uncomplicated post-transplant disease course. Four patients did not consistently retain complete donor chimerism; two of them relapsed within the next 3 months, one died from septicemia within 7 days, and the fourth, transplanted for aplastic anaemia, is still in complete remission. Overall, STR analysis using a simple and comparatively cheap multiplex system permits the detection of chimerism very early after transplantation and may provide relevant information that correlates with the clinical follow-up. [source]

Mixed chimerism and graft failure following conditioning with the fludarabine and cyclophosphamide nonablative regimen; Conversion to full donor chimerism

AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2007
Anand P. Jillella
Abstract Twenty-one patients with hematologic malignancies were treated with the fludarabine (120,125 mg/m2) and cyclophosphamide (120 mg/kg) nonmyeloablative conditioning regimen. Graft versus host disease (GVHD) and graft rejection prophylaxis was with tacrolimus and mycophenolate mofetil. Thirteen of the 21 patients (62%) had mixed chimerism (,,90% donor cells) at day 60 and 11 (52%) of these patients had mixed chimerism which persisted until day 100. Immunosuppression was discontinued in 12 of 13 patients and two of them converted to full chimerism by day 100. Eight patients received a donor lymphocyte infusion (DLI) and five of them converted to full donor chimerism with DLI alone. Two patients were given GM-CSF in addition to a DLI with conversion to full donor chimerism. Three patients (14%) had graft failure requiring a second transplant using fludarabine (125 mg/m2) and melphalan (140 mg/m2). With a median followup of 2.8 years, 15 patients are alive,one with disease and 14 with no disease. Two patients died of acute GVHD, one of chronic GVHD, and three due to progressive disease. We conclude that the nonmyeloablative fludarabine/cyclophosphamide regimen results in a significant incidence of mixed chimerism and graft rejection but is well tolerated. We suggest a more intense regimen, such as fludarabine and melphalan, be used in patients with a high risk of early disease progression to establish early engraftment and graft versus tumor effect. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source]

Molecular monitoring of T-cell chimerism early after allogeneic stem cell transplantation may predict the occurrence of acute GVHD grades II,IV

CLINICAL TRANSPLANTATION, Issue 3 2005
Marie Jaksch
Abstract:, Mixed chimerism (MC) within CD4+ and CD8+ T cell days 7 and 10 after allogeneic stem cell transplantation (SCT) was compared with the occurrence of acute graft-vs.-host disease (GVHD) in 34 patients after SCT. Acute GVHD was diagnosed in 22 patients within the first 3 months after SCT, 15 of these developed acute GVHD grades II,IV. The difference in the clearance rate of host T cell between the two days were compared. We found a significantly higher risk (p = 0.005) for developing acute GVHD grades II,IV in patients with complete donor CD4+ T-cell chimerism day 7 after SCT together with patients who increased 50% or more in donor CD4+ T cells between days 7 and 10 after SCT. Our data suggest that molecular monitoring of MC early after transplantation may be useful as a diagnostic tool in predicting the occurrence of moderate to severe acute GVHD after SCT. [source]

Sustained and stable hematopoietic donor-recipient mixed chimerism after unrelated cord blood transplantation for adult patients with severe aplastic anemia

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2005
P. Mao
Abstract:, We evaluated the engraftment of donor cells from unrelated cord blood into adult patients with severe aplastic anemia (SAA) and the outcome of allo-CBSCT (cord blood stem cell transplantation). Nine patients were conditioned with decreased dosage of immunosuppressive agents of CTX (60 mg/kg) and ALG (120 mg/kg). The prophylaxis of GVHD consisted of standard CsA and MTX. Patients have a media age of 25.3 yr (range: 15,37), and a median weight of 57.2 kg (range: 52.5,60) at the time of transplantation. Cord blood searches were all conducted at Guangzhou Cord Blood Bank. The engraftment state of the donor cells into recipients was confirmed by microsatellite DNA fingerprinting and fluorescent quantitative PCR analysis. Engrafted evidence has been found in seven patients involved by biomolecular analyses showing donor-recipient mixed chimerism post-transplant which was stable and persistent. After a median follow up of 32.2 months (range: 4,69), seven patients were alive and disease free. This study shows that durable donor-recipient stable mixed chimerism can be achieved by unrelated CBSCT in patients with SAA. Umbilical cord blood could be employed as a source of hematopoietic stem cell for adult transplantation. [source]

Simultaneous administration of a low-dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long-term survival of cardiac allograft in rats

IMMUNOLOGY, Issue 2 2003
Yongzhu Jin
Summary T-cell costimulatory blockade combined with donor bone marrow transfusion may induce mixed chimerism, rendering robust tolerance in transplanted organs and cells. However, most protocols entail high doses of donor bone marrow cells (BMCs) or repeated administration of costly agents that block costimulatory pathways, thus delaying clinical development. To circumvent these shortcomings, we developed a strategy in which the dosage of donor BMCs was reduced but compensated by donor splenocytes (SPLCs). Furthermore, repeated administration of costly agents was replaced with a single injection of adenovirus expressing a gene of interest. In rat cardiac transplantation models, cardiac allografts from DA (RT-1a) rats were transplanted heterotopically into the abdomen of LEW (RT-11) recipient rats. Immediately after cardiac transplantation, an adenovirus vector (AdCTLA4Ig; 5 × 109 plaque-forming units) containing the gene for CTLA4Ig was administered to recipients (n = 6) simultaneously with a low dose of donor BMCs (1 × 108/rat) and SPLCs (5 × 107/rat) via the portal vein. The treated LEW recipient rats developed long-lasting mixed chimerism (>10% at >100 days) and exhibited long-term cardiac allografts (mean survival time of > 200 days) compared with control recipients. Moreover, recipients displaying long-lasting mixed chimerism accepted subsequent donor skin allografts while promptly rejecting third-party skin allografts. These results suggest that blockade of the CD28-B7 pathway, using adenovirus-mediated CTLA4Ig gene transfer, in concert with a low dosage of donor BMCs and SPLCs, may represent a feasible strategy to induce stable mixed chimerism and permit long-term survival of cardiac allografts. [source]

Successful unrelated mismatched cord blood transplantation in an infant with severe combined immunodeficiency and Mycobacterium bovis bacillus Calmette-Gučrin disease

PEDIATRIC TRANSPLANTATION, Issue 4 2006
Tang-Her Jaing
Abstract:, The case reported here of an infant who presented with Pneumocystis carinii pneumonia, CD4+ lymphopenia, and hypogammaglobulinemia attributable to severe combined immunodeficiency (SCID). This report discussed treatment of Mycobacterium bovis bacillus Calmette-Gučrin disease with unrelated cord blood transplantation in addition to antituberculous therapy, by adoptively transferring donor immunity with induction of mixed chimerism. Because of the unique nature of umbilical cord blood hematopoietic cells, engraftment without conditioning may be possible in SCID patients without fully matched donors. [source]

Mixed chimerism and graft failure following conditioning with the fludarabine and cyclophosphamide nonablative regimen; Conversion to full donor chimerism

AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2007
Anand P. Jillella
Abstract Twenty-one patients with hematologic malignancies were treated with the fludarabine (120,125 mg/m2) and cyclophosphamide (120 mg/kg) nonmyeloablative conditioning regimen. Graft versus host disease (GVHD) and graft rejection prophylaxis was with tacrolimus and mycophenolate mofetil. Thirteen of the 21 patients (62%) had mixed chimerism (,,90% donor cells) at day 60 and 11 (52%) of these patients had mixed chimerism which persisted until day 100. Immunosuppression was discontinued in 12 of 13 patients and two of them converted to full chimerism by day 100. Eight patients received a donor lymphocyte infusion (DLI) and five of them converted to full donor chimerism with DLI alone. Two patients were given GM-CSF in addition to a DLI with conversion to full donor chimerism. Three patients (14%) had graft failure requiring a second transplant using fludarabine (125 mg/m2) and melphalan (140 mg/m2). With a median followup of 2.8 years, 15 patients are alive,one with disease and 14 with no disease. Two patients died of acute GVHD, one of chronic GVHD, and three due to progressive disease. We conclude that the nonmyeloablative fludarabine/cyclophosphamide regimen results in a significant incidence of mixed chimerism and graft rejection but is well tolerated. We suggest a more intense regimen, such as fludarabine and melphalan, be used in patients with a high risk of early disease progression to establish early engraftment and graft versus tumor effect. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source]

Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010
N. Pilat
Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-, induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach. [source]

Recipient Dendritic Cells, But Not B Cells, Are Required Antigen-Presenting Cells for Peripheral Alloreactive CD8+ T-Cell Tolerance

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010
J. L. Mollov
Induction of mixed allogeneic chimerism is a promising approach for achieving donor-specific tolerance, thereby obviating the need for life-long immunosuppression for solid organ allograft acceptance. In mice receiving a low dose (3Gy) of total body irradiation, allogeneic bone marrow transplantation combined with anti-CD154 tolerizes peripheral CD4 and CD8 T cells, allowing achievement of mixed chimerism with specific tolerance to donor. With this approach, peripheral CD8 T-cell tolerance requires recipient MHC class II, CD4 T cells, B cells and DCs. Recipient-type B cells from chimeras that were tolerant to donor still promoted CD8 T-cell tolerance, but their role could not be replaced by donor-type B cells. Using recipients whose B cells or DCs specifically lack MHC class I and/or class II or lack CD80 and CD86, we demonstrate that dendritic cells (DCs) must express CD80/86 and either MHC class I or class II to promote CD8 tolerance. In contrast, B cells, though required, did not need to express MHC class I or class II or CD80/86 to promote CD8 tolerance. Moreover, recipient IDO and IL-10 were not required. Thus, antigen presentation by recipient DCs and not by B cells is critical for peripheral alloreactive CD8 T cell tolerance. [source]

Fatal Graft-Versus-Host Disease Presenting as Fever of Unknown Origin in a Pancreas-After-Kidney Transplant Recipient

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2008
F. L. Weng
Acute graft-versus-host disease (GVHD) is a rare complication of pancreas transplantation. We describe a 54-year-old male with type 1 diabetes who received a zero-antigen mismatched pancreas-after-kidney transplant from a pancreas donor who was homozygous at the HLA-B, -Cw, -DR, and -DQ alleles. Starting on postoperative day (POD) #22, the patient developed persistent fevers. Workup was notable only for low-grade cytomegalovirus viremia, which was treated. The fevers eventually disappeared. On POD #106, the patient was noted to have a diffuse erythematous rash. A skin biopsy was consistent with GVHD. Short tandem repeat DNA analysis of both peripheral blood lymphocytes and skin demonstrated mixed chimerism, confirming the diagnosis of GHVD. Soon after diagnosis, the patient developed pancytopenia and fevers and died of multiorgan failure on POD #145. Transplant clinicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants. [source]

Capillary electrophoresis for chimerism monitoring by PCR amplification of microsatellite markers after allogeneic hematopoietic cell transplantation

CLINICAL TRANSPLANTATION, Issue 3 2005
Alexandros Spyridonidis
Abstract:, Background:, Hematopoietic chimerism has been demonstrated to be relevant for donor cell engraftment and detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). In the light of increasing numbers of non-myeloablative aHCT as a treatment modality sensitive, rapid, and accurate chimerism monitoring techniques acquire novel relevance. Methods:, We evaluated the informativeness of five microsatellite markers in 376 donor/recipient pairs and evaluated the ability of capillary electrophoresis to detect mixed chimerism after aHCT. The sensitivity for capillary electrophoresis with respect to different markers was determined by limiting dilution assays with mixed chimerism samples containing defined amounts of cells or DNA. Furthermore, capillary electrophoresis was applied in 17 retrospectively selected patients with a mixed chimerism detected previously by gel electrophoresis, having undergone aHCT for different hematologic diseases and initially achieving a complete donor chimerism. Results:, In 163 of 165 (98%) of all related and 210 of 211 (99%) unrelated transplants the microsatellites identified informative alleles. The sensitivity and accuracy was higher with capillary electrophoresis when compared with gel electrophoresis with three of five microsatellites. Potential pitfalls with the application of capillary electrophoresis was preferential amplification and the occurrence of stutter peaks in the representative area. Investigation of the selected patient samples demonstrated that detection of a mixed chimerism was earlier with capillary electrophoresis when compared with gel electrophoresis. The detected recipient genotype by capillary electrophoresis examination, despite a negative gel electrophoresis result, ranged from 0.7 to 7.1%. Conclusions:, We conclude that chimerism assessment with our five microsatellites identified informative alleles in 99% of all donor/recipient pairs and may therefore be of use when establishing an institutional chimerism testing procedure. Capillary electrophoresis displayed a high sensitivity and accuracy for detecting a mixed chimerism in vitro and in vivo. [source]