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1.
Hematology ; 26(1): 435-443, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34130602

RESUMO

A retrospective study on 287 patients with SAA who underwent allo-HSCT between October 2012 and January 2020 was conducted to explore the outcomes, risk factors and treatment options for MC. Among 287 AA patients who excluded Fanconi anemia (FA), Congenital dyskeratosis (DKC), Paroxysmal nocturnal hemoglobinuria (PNH), etc.112 underwent matched sibling donor (MSD)-HSCT, 91 matched unrelated donor-HSCT and 84 haploidentical-HSCT. Patients were divided into the following 4 groups: group 1: Donor chimerism (DC); group 2: MC without cytopenia; group 3: MC with cytopenia; group 4: secondary graft failure (SGF).Compared with the other three groups, SGF predicted a poor prognosis of SAA (P< 0.001). In addition, SGF was associated with the early (within 3 months after transplantation) presence of MC and the high levels of MC. Uni- and multivariate logistic regression analysis showed that donor/recipient sex-mismatching and CTX + ATG regimen were high-risk factors for MC. Of note, in MC patients with cytopenia (group 3), the effective response rate reached 55% (6/11) following enhanced immunosuppression combined with cellular therapy, while only one of the four was effective who received enhanced immunosuppression alone.SGF was associated with poor prognosis, early presence of MC and increased levels of recipient chimerism. The donor/recipient sex-mismatching and CTX + ATG regimen based MSD-HSCT were risk factors for MC. Cellular therapy could improve the effective response rate of patients with progressive MC.


Assuntos
Anemia Aplástica/terapia , Quimerismo , Transplante de Células-Tronco Hematopoéticas , Adulto , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos
2.
Transplant Cell Ther ; 27(4): 316.e1-316.e8, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836874

RESUMO

Immune-mediated cytopenias (IMC)-isolated or combined hemolytic anemia, thrombocytopenia, or neutropenia-are increasingly recognized as serious complications after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant disorders (NMD). However, IMC incidence, duration, response to therapy, and risk factors are not well defined. This retrospective chart review identified cases of IMC with serologic confirmation among patients who underwent HCT for NMD at a single institution between 2010 and 2017. IMC after HCT for NMD in a large pediatric cohort (n = 271) was common with a cumulative incidence of 18%, identified at a median of 136 days after HCT. Treatment included prolonged immune suppression (>3 months) in 58% of all IMC cases, 91% when multiple cell lines were affected. Multiple therapeutic agents were used for the majority affected, and median time to resolution of IMC was 118 days from diagnosis. Fine-Gray competing risk multivariate regression analysis identified a combined risk factor of younger age (<3 years) and inherited metabolic disorder, as well as hemoglobinopathy (at any age) associated with 1-year incidence of IMC (P < .01). We expand these findings with the observation of declining donor T-lymphoid chimerism from day 60 to 100 and lower absolute CD4+ counts at day 100 (P < .01), before median onset of IMC, for patients with IMC compared to those without. In this cohort, 4 deaths (8%) were associated with IMC, including 2 requiring second transplantation for secondary graft failure. Although the pathogenesis of IMC post-HCT for NMD remains elusive, further research may identify approaches to prevent and better treat this HCT complication.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Trombocitopenia , Criança , Pré-Escolar , Quimerismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Condicionamento Pré-Transplante
3.
Front Immunol ; 12: 607282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854497

RESUMO

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.


Assuntos
Modelos Animais de Doenças , Xenoenxertos , Sistema Imunitário , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Quimerismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/etiologia , Fenótipo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Transplant Proc ; 53(4): 1360-1364, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33888344

RESUMO

Acute myeloid leukemia (AML) is a rare malignancy with increased incidence in the kidney transplantation (KT) population for which immunosuppression has been implicated as a putative cause. The average time interval from KT to AML development is 5 years. We present the case of a 61-year-old man who was found to have peripheral blood blasts on a postoperative day 20 routine blood draw after an uneventful unrelated living donor kidney transplant. He subsequently had a bone marrow biopsy and next-generation sequencing (NGS)-based molecular testing, which demonstrated AML characterized by SMC1A and TET2 mutations. He received induction chemotherapy followed by hematopoietic cell transplantation (HCT) from the kidney donor, who happened to be matched at one haplotype. At 12 months after his HCT and 15 months after his KT, his AML remained in remission, normal renal function was preserved, no active graft-versus-host disease was present, and immunosuppression was tapering. With full donor-derived hematopoietic chimerism, we expect to be able to discontinue immunosuppression shortly, thereby achieving tolerance. The short time interval between KT and development of AML suggests the malignancy was likely present before KT. Modern NGS-based analysis offers a promising method of identifying transplant candidates with unexplained hematologic abnormalities on pre-KT testing who may benefit from formal hematologic evaluation.


Assuntos
Transplante de Rim/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Medula Óssea/patologia , Proteínas de Ciclo Celular/genética , Quimerismo , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Doença Enxerto-Hospedeiro/etiologia , Haplótipos , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/genética , Indução de Remissão
5.
Blood Adv ; 5(6): 1605-1616, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33710339

RESUMO

Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38-CD45RA-CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38-CD45RA-CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was >50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Animais , Ciclo Celular , Quimerismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Mitocôndrias
6.
Transplant Cell Ther ; 27(3): 257.e1-257.e6, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781527

RESUMO

Fanconi anemia (FA) cells are characterized by genomic instability, which places FA patients at risk for malignancies such as leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT). Mixed chimerism (MC) in FA patients might have a unique implication because the persistent existence of FA cells might give rise to a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome according to chimerism status. Patients with FA who had evidence of progressive bone marrow failure and were blood products-transfusion dependent (packed red blood cells, platelets, or both) were included in the study. Those who had myelodysplasia (MDS) or an abnormal clone or evidence of leukemia were excluded. All but 3 patients had normal renal and cardiac function at the time of transplantation. In total, 160 patients with FA underwent allogeneic HCT at our center from January 1995 to December 2017; mean age at HCT was 8.4. Chimerism data at last follow-up visit were available on 97 patients who are the subjects of this analysis (no day +100 chimerism data on one of them). On day +100, 46 patients (47.9%) had full chimerism (FC) and 50 (52.1%) had MC, whereas at last follow-up 50 (51.5%) exhibited FC and the remaining 47 (48.5%) had MC. Cumulative incidence of all grades acute graft-versus-host disease (GVHD) was 13.4% and that of grade III to IV GVHD was 4.1%. Chronic GVHD was seen in eight (8.0%) patients. Incidence of severe acute GVHD (grade ≥ III) and that of chronic GVHD were not significantly associated with FC or MC measured at day +100 (P values = .347 and .254, respectively), nor at the last follow-up. Graft failure occurred in 2 patients; both from the MC at day +100 group. No graft failures occurred in the FC at day +100 group (P value = 1.00). At a median follow-up of 83.8 months (95% confidence interval, 51.0-116.6; range, 19.3-181.1 months) the cumulative probability of overall survival (OS) at 5 years was 95.7% ± 2.1%. Mean follow-up time in our cohort was 90.7 months. Five-year overall survival was not significantly associated with FC or MC evaluated at day +100 (95.7% ± 3.0% versus 95.6% ± 3.1%, P value = .908) nor at the last follow-up (96.0% ± 2.8% versus 95.4% ± 3.2%, P value = .925). No patient in either group developed MDS/leukemia during the follow-up period. We conclude that mixed chimerism in patients with FA appears to have no adverse effect on outcome in our follow-up period. A longer follow-up period is needed, however, to confirm the validity of this statement.


Assuntos
Anemia de Fanconi , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Criança , Quimerismo , Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Condicionamento Pré-Transplante
7.
Transplant Cell Ther ; 27(3): 258.e1-258.e6, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781528

RESUMO

The overall objective of allogeneic hematopoietic cell transplantation (HCT) in patients with non-malignant conditions involves replacing a dysfunctional or absent cell or gene product for disease correction. It is unclear whether lower busulfan exposure may be sufficient in this population to facilitate durable myeloid engraftment and limit toxicity. Given that neither the ideal level of mixed myeloid chimerism for specific non-malignant diseases nor how to condition a patient to achieve stable mixed myeloid chimerism is fully known, we sought to analyze the relationships among busulfan exposure, myeloid chimerism, and outcomes in patients with non-malignant conditions receiving busulfan as a part of combination pretransplant conditioning at our institution. This was a single-center, retrospective study including pediatric patients with a variety of non-malignant disorders who underwent allogeneic HCT at the University of California San Francisco Benioff Children's Hospital from March 2007 to June 2018. The busulfan cumulative area under the curve (cAUC) was estimated using a validated population pharmacokinetic model and nonlinear mixed effects modeling. Median busulfan cAUC for all patients was 70 mg·h/L (range, 53 to 108). All of the 29 patients with a busulfan cAUC of ≥70 mg·h/L achieved long-term disease correction with full or stable mixed (>20%) myeloid chimerism, compared to 78.5% (22/28) of patients with a cAUC of <70 mg·h/L (P = .01). Overall ksurvival was evaluated up to 3 years and was identical in patients with busulfan cAUC < 70 mg·h/L and patients with busulfan cAUC ≥70 mg·h/L (96% versus 93%; P = .92). Only three patients died, at days 65, 164 and 980 days post-HCT. Severe busulfan-related toxicities and graft-versus-host-disease (GVHD) were rare, with veno-occlusive disease occurring in four patients (7%), acute respiratory distress syndrome in three patients (5%), and GVHD in five patients (9%). These results demonstrate excellent outcomes and extremely low rates of toxicity across our entire cohort. Based on the results of this study, we recommend a busulfan exposure target of 75 mg·h/L (range, 70 to 80) in all non-malignant patients receiving allogeneic HCT to ensure optimal exposure for achievement of high-level stable myeloid chimerism.


Assuntos
Bussulfano , Quimerismo , Bussulfano/efeitos adversos , Criança , Humanos , Estudos Retrospectivos , São Francisco , Condicionamento Pré-Transplante
8.
Transfusion ; 61(4): 1041-1046, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33528026

RESUMO

BACKGROUND: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature. STUDY DESIGN AND MATERIALS: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia. RESULTS: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin. CONCLUSION: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.


Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Anticorpos Monoclonais/farmacologia , Transplante de Medula Óssea/métodos , Função Retardada do Enxerto/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/deficiência , Doenças da Imunodeficiência Primária/terapia , Adolescente , Assistência ao Convalescente , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Quimerismo , Eritrócitos/imunologia , Feminino , Hemaglutininas/sangue , Hemaglutininas/efeitos dos fármacos , Humanos , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Aplasia Pura de Série Vermelha/tratamento farmacológico , Transplante Haploidêntico/efeitos adversos , Resultado do Tratamento
9.
Transfusion ; 61(3): 960-967, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33638187

RESUMO

BACKGROUND: A 30-year-old man underwent double umbilical cord blood transplantation (UCBT) for acute myeloid leukemia (AML) with reduced intensity conditioning. The cords had identical HLA types and were each a 5/6 match to the patient. Following transplantation, cord 2 initially dominated all tested cell populations. At day +306, we observed an unusual reversal of dominance chimerism pattern in which cord 1 instead dominated all tested populations. STUDY DESIGN & METHODS: Polymerase chain reaction (PCR)-based short tandem repeat (STR) assays were performed on the peripheral blood and bone marrow samples. The white blood cell (WBC) populations from the peripheral blood were manipulated for testing to create subpopulations enriched for CD3, CD33, and CD56. RESULTS: Chimerism studies on day +77 showed the following: cord 1: 44%-CD3; 0%-CD33; 16%-CD56; cord 2: 56%-CD3; 100%-CD33; 84%-CD56. Cord 2 initially dominated in all tested cell populations. Chimerism studies performed on post-transplantation day +306 uncovered a reversal of dominance chimerism pattern in which cord 1 now dominated in all cell populations (cord 1: 82%-CD3; >95%-CD33; 67%-CD56; cord 2: 18%-CD3; <5%-CD33; 33%-CD56). Between days +127 and +244, the patient's blood type shifted from B Rh-positive to A Rh-negative. CONCLUSION: The change in the patient's blood type identified a late reversal of dominance chimerism pattern. This is a rare occurrence, previously cited only once, which is inconsistent with published data that early high CD3 counts and unseparated bone marrow chimerism predominance at day +100 predict long-term cord dominance in double UCBT in the vast majority of cases.


Assuntos
Quimerismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/terapia , Leucócitos/metabolismo , Adulto , Tipagem e Reações Cruzadas Sanguíneas , Medula Óssea/metabolismo , Complexo CD3/sangue , Complexo CD3/genética , Antígeno CD56/sangue , Antígeno CD56/genética , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Reação em Cadeia da Polimerase , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética
10.
J Transl Med ; 19(1): 15, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407582

RESUMO

BACKGROUND: Non-invasive molecular analysis of cell-free DNA (cfDNA) became a sensitive biomarker for monitoring organ transplantation or for detection of fetal DNA (cffDNA) in noninvasive prenatal test. In this study, we compared the efficiencies of four (semi)-automated cfDNA isolation instruments using their respective isolation kit: MagNA Pure 24 (Roche®), IDEAL (IDSolution®), LABTurbo 24 (Taigen®) and Chemagic 360 (Perkin Elmer®). The cfDNA was isolated from 5 plasma samples and the Rhesus D (RhD)-cffDNA from 5 maternal plasmas. The cfDNA were quantified by digital droplet PCR (ddPCR), BIABooster system and QUBIT fluorometer. The cfDNA fragment size profiles were assessed by BIABooster system. Chimerism were quantified by home-made ddPCR and Devyser NGS kit. RhD-cffDNA in maternal plasma were detected between weeks 14 and 24 of amenorrhea using free DNA Fetal RHD Kit® (Biorad®). RESULTS: Statistical tests have shown differences in DNA yield depending on the isolation procedure and quantification method used. Magna Pure isolates smaller cfDNA fragment size than other extraction methods (90% ± 9% vs. 74% ± 8%; p = 0.009). Chimerism was only reliable from LABTurbo 24 extractions using the NGS but not with ddPCR whatever extraction methods. RhD-cffDNA were detected by all isolation methods, although IDEAL and LABTurbo 24 systems seemed more efficient. CONCLUSIONS: This comparative study showed a dependency of cfDNA yield depending on isolation procedure and quantification method used. In total, these results suggest that the choice of pre-analytical isolation systems needs to be carefully validated in routine clinical practice.


Assuntos
Ácidos Nucleicos Livres , Teste Pré-Natal não Invasivo , Quimerismo , DNA , Feminino , Feto , Humanos , Gravidez , Diagnóstico Pré-Natal
11.
Eur J Cardiothorac Surg ; 60(1): 194-196, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-33495782

RESUMO

Graft-versus-host disease (GVHD), a serious complication of haematopoietic stem cell transplantation, can occur following solid organ transplantation. However, diagnosing solid organ transplantation-associated GVHD is difficult, and its risk factors are not fully understood. Here, we report a GVHD case in a 59-year-old woman with dermatomyositis-associated interstitial pneumonia, who took immunosuppressants including corticosteroids before receiving right lung transplantation from a 13-year-old brain-dead male donor. She developed systemic erythema with desquamation and pancytopenia by day 20. Mixed chimerism with donor- and recipient-type cells in the bone marrow and skin led to the diagnosis of GVHD. Corticosteroid pulse therapy reduced the symptoms and decreased donor-type cell percentage. On day 50, the patient developed donor lung injury and was diagnosed with acute rejection, which was treated using steroid pulse therapy again. Although the granulocytes were recipient type, donor chimerism of peripheral blood T cells exacerbated on day 68. Subsequent deterioration of liver function and pulmonary injury in the patient's own lung led to the diagnosis of relapsing GVHD. The patient died of multiple organ failure despite treatment with anti-thymocyte globulin. Thus, repeated steroid pulse therapy and age difference between donors and recipients may predispose to GVHD and T-cell mixed chimerism can be an important diagnostic indicator of GVHD.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Órgãos , Adolescente , Transplante de Medula Óssea , Quimerismo , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T
13.
Ann N Y Acad Sci ; 1487(1): 12-20, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32991755

RESUMO

Organ and tissue repair are complex processes involving signaling molecules, growth factors, and cell cycle regulators that act in concert to promote cell division and differentiation at sites of injury. In embryonic development, progenitor fetal cells are actively involved in reparative mechanisms and display a biphasic interaction with the mother; and there is constant trafficking of fetal cells into maternal circulation and vice versa. This phenomenon of fetal microchimerism may have significant impact considering the primitive, multilineage nature of these cells. In published work, we have reported that fetal-derived placental cells expressing the homeodomain protein CDX2 retain all "stem" functional proteins of embryonic stem cells yet are endowed with additional functions in areas of growth, survival, homing, and immune modulation. These cells exhibit multipotency in vitro and in vivo, giving rise to spontaneously beating cardiomyocytes and vascular cells. In mouse models, CDX2 cells from female placentas can be administered intravenously to male mice subjected to myocardial infarction with subsequent homing of the CDX2 cells to infarcted areas and evidence of cellular regeneration with enhanced cardiac function. Elucidating the role of microchimeric fetal-derived placental cells may have broader scientific potential, as one can envision allogeneic cell therapy strategies targeted at tissue regeneration for a variety of organ systems.


Assuntos
Quimerismo/embriologia , Regeneração/fisiologia , Cicatrização/fisiologia , Animais , Feminino , Feto/imunologia , Feto/metabolismo , Humanos , Masculino , Troca Materno-Fetal/fisiologia , Camundongos , Transplante de Órgãos/métodos , Transplante de Órgãos/tendências , Gravidez , Regeneração/genética , Regeneração/imunologia , Medicina Regenerativa/métodos , Medicina Regenerativa/tendências , Transdução de Sinais/fisiologia , Cicatrização/genética , Cicatrização/imunologia
16.
Forensic Sci Int ; 318: 110639, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33307471

RESUMO

Identification of an individual is the prime object in forensic case works both in civil or criminal situations like paternity/maternity disputes, sexual assaults, murder, mass disaster victims etc. STR analysis has already proved its potential to give accurate results. In addition to autosomal chromosomes, sex determination at many times is crucial in forensic situations, especially in situations like rape cases or in cases of missing persons. The chances of wrong interpretations may arise due to false detection (or non-detection) of STR fragments overall or only at amelogenin-specific fragments, in situation like mutations, intersex conditions, trans-sexualism etc., due to natural or artificial chimersim. The forensic relevance of the possible misinterpretation of STR's or amelogenin should never be underestimated. The present study was carried out to identify an individual using Y-STR in sex mismatch patients who received hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation is a method to replace patient's stem cell with the stem cell donated by the donor preferably biological related in order to cure malignant and non malignant diseases. This study enrolled ten female patients of HSCT. Samples were collected as pre and post transplant after 15 days, 30 days, 60 days, and 90 days of time interval from sex mismatch patient (female) and from donor (male) and chimeric status of the patient was analyzed using Y-STR markers (23 loci). Results demonstrated that donor genotype existed in blood and buccal swab of the recipient but no genetic profile existed for Y-STR in hair follicle of the recipient. This study suggests that only hair follicle out of three biological samples tested serves as reliable source of recipient's origin after HSCT for accurate personal identification especially in forensic situations.


Assuntos
Quimerismo , Cromossomos Humanos Y , Impressões Digitais de DNA/métodos , Transplante de Células-Tronco Hematopoéticas , Repetições de Microssatélites , Análise Química do Sangue , Células Epiteliais/química , Feminino , Folículo Piloso/química , Humanos , Masculino , Mucosa Bucal/citologia , Processos de Determinação Sexual , Doadores de Tecidos , Transplantados
17.
Forensic Sci Int ; 318: 110636, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33307474

RESUMO

The use of biological traces recovered from touched or handled items increased with the advance of the forensic analysis system. Thus, DNA profiles obtained from touch DNA became a useful tool in forensic investigation. However, a chimeric person with more than one chromosomal population can be challenging for a forensic analyst. We investigated the genetic profile in blood, buccal swab, and skin swabs from twenty-four recipients aged 21-63 years who underwent a matched sibling allogeneic hematopoietic stem cell transplantation with no sign of skin graft versus host disease. Autosomal short tandem repeats genotyping was performed to evaluate chimerism status at 15 loci along with gender marker Amelogenin. According to our results, donor chimerism was detected in all recipient's blood samples, while in buccal swabs, five recipients showed no presence of donor-derived cells in their genotype. Epithelial cells swabbed from hand fingertips were not devoid of donor-derived cells since all recipients showed high chimerism (39.69%-96.66%) in their genotypes. A significant change in chimerism was seen among various types of biological samples (p<0.05). No correlations were observed between chimerism and recipient age, gender, or time after transplant (p> 0.05). The loci D21S11, D8S1179, and FGA were the most informative, whereas D13S317, Vwa, and TOPX were the least informative STR markers. We concluded that touch DNA from a person who has undergone a successful allogeneic HSCTs should not be considered as reliable evidence for human identifications. Therefore, necessary precautions must be taken to avoid false identification and miscarriage of justice.


Assuntos
Quimerismo , Impressões Digitais de DNA , Transplante de Células-Tronco Hematopoéticas , Pele/citologia , Transplantados , Transplante Homólogo , Adulto , Células Epiteliais/química , Feminino , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Estudos Prospectivos , Tato , Adulto Jovem
18.
Clin Transplant ; 35(2): e14160, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33222318

RESUMO

OBJECTIVES: The aim of our study was to determine possible predictors and clinical course of mixed chimerism (MC) in aplastic anemia after transplantation. METHODS: A total of 207 transplants were obtained from haploidentical donors (HID) using busulfan (Bu), cyclophosphamide (Cy), and anti-thymocyte globulin (ATG) regimens, and 69 transplants from matched related donors (MRD) and 29 transplants from unrelated donors (URD) using Cy/ATG regimens were obtained. RESULTS: Incidences of MC were 1.93 ± 0.01%, 20.29 ± 0.01%, and 35.71 ± 0.01% in HID, MRD, and URD transplantation (p < .001). In multivariate analysis, incidence of MC was significantly higher in patients without adding Bu in conditioning (p < .001) and receiving a lower number of CD3 + cells in graft (p = .042). MC was associated with significantly lower II-IV aGvHD (3.70% vs. 27.7%, p = .007), but higher secondary graft rejection rates (14.8% vs. 0.4%, p < .001) and poorer overall survival (72.7 ± 8.9% vs. 89.6 ± 2.0%, p = .011) than those of donor chimerism cohort. CONCLUSIONS: Mixed chimerism was an unsettling status even in non-malignancy. Haploidentical transplantation with more intense regimen by adding Bu to Cy and ATG was associated with reduced MC following HSCT for SAA. An intensified regimen should be explored in matched related or unrelated donors.


Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/terapia , Quimerismo , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Fatores de Proteção , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento
19.
Clin Chim Acta ; 512: 40-48, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33227269

RESUMO

The aim of this study was to evaluate the performance of a novel NGS-based assay to monitor mixed chimerism (MC) and compare its technical capacity to established techniques for chimerism analysis. Artificial and clinical samples with increasing amounts of patient DNA were compared using real-time PCR detection of indels and SNP, fragment analysis of short-tandem repeats (STR) and NGS analysis of indels. Real-time PCR displayed excellent sensitivity (>0,01%) but poor accuracy (>20 CV% at MC > 20%), while fragment analysis exhibited good accuracy (<5 CV% at MC > 20%) with limited sensitivity (>2,5%). In contrast, NGS chimerism demonstrated a sensitivity (>0,1%) equal to real-time PCR and an accuracy equal or better than STR analysis throughout an extensive range of mixed chimerism (0,1 - 100%). To evaluate performance of the separate techniques for chimerism determination, 75 retrospective patient monitoring samples (3-7 weeks post-HSCT) with low (<5%), intermediate (5-20%) or high mixed chimerism (>20%) were analyzed. The between run precision for the NGS assay varied from 0,72% (>20% MC) to 7,38% (MC < 5%). In conclusion, NGS displayed a combination of high sensitivity with good accuracy in both artificial and clinical chimerism samples.


Assuntos
Quimerismo , Transplante de Células-Tronco Hematopoéticas , DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Repetições de Microssatélites , Estudos Retrospectivos , Quimeras de Transplante
20.
Am J Transplant ; 21(3): 968-977, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32633070

RESUMO

Eliminating cytoreductive conditioning from chimerism-based tolerance protocols would facilitate clinical translation. Here we investigated the impact of major histocompatibility complex (MHC) and minor histocompatibility antigen (MiHA) barriers on mechanisms of tolerance and rejection in this setting. Transient depletion of natural killer (NK) cells at the time of bone marrow (BM) transplantation (BMT) (20 × 106 BALB/c BM cells → C57BL/6 recipients under costimulation blockade [CB] and rapamycin) prevented BM rejection. Despite persistent levels of mixed chimerism, BMT recipients gradually rejected skin grafts from the same donor strain. Extending NK cell depletion did not improve skin graft survival. However, F1 (C57BL/6×BALB/c) donors, which do not elicit NK cell-mediated rejection, induced durable chimerism and tolerance. In contrast, if F1 donors with BALB/c background only were used (BALB/c×BALB.B), no tolerance was observed. In the absence of MiHA disparities (B10.D2 donors, MHC-mismatch only), temporal NK cell depletion established stable chimerism and tolerance. Conversely, MHC identical BM (BALB.B donors, MiHA mismatch only) readily engrafted without NK cell depletion but no skin graft tolerance ensued. Therefore, we conclude that under CB and rapamycin, MHC disparities provoke NK cell-mediated BM rejection in nonirradiated recipients whereas MiHA disparities do not prevent BM engraftment but impede skin graft tolerance in established mixed chimeras.


Assuntos
Quimerismo , Tolerância Imunológica , Animais , Transplante de Medula Óssea , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante de Pele , Quimeras de Transplante , Tolerância ao Transplante
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