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1.
Ann Hematol ; 100(11): 2787-2797, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34476574

RESUMO

Haploidentical transplantation has extended the availability of allogeneic hematopoietic stem cell transplant (alloHCT) to almost all patients. Sequential conditioning regimens have been proposed for the treatment of hematological active disease. Whether these new transplantation procedures affect the prognosis of critically ill alloHCT recipients remains unknown. We evaluated this question in a retrospective study including consecutive alloHCT patients admitted to the intensive care unit of a tertiary academic center from 2010 to 2017. During the study period, 412 alloHCTs were performed and 110 (27%) patients-median age 55 (36-64) years-were admitted to ICU in a median time of 58.5 (14-245) days after alloHCT. Twenty-nine (26%) patients had received a haploidentical graft and 34 (31%) a sequential conditioning. Median SOFA score was 9 (6-11). Invasive mechanical ventilation (MV) was required in 61 (55%) patients. Fifty-six (51%) patients died in the hospital. Independent factors associated with in-hospital mortality were as follows: MV (OR=8.44 [95% CI 3.30-23.19], p<0.001), delta SOFA between day 3 and day 1 (OR=1.60 [95% CI 1.31-2.05], p<0.0001), and sequential conditioning (OR=3.7 [95% CI 1.14-12.92], p=0.033). Sequential conditioning was also independently associated with decreased overall survival (HR=1.86 [95% CI 1.05-3.31], p=0.03). Other independent factors associated with reduced overall survival were HCT-specific comorbidity index ≥2 (HR=1.76 [95% CI 1.10-2.84], p=0.02), acute GVHD grade ≥2 (HR=1.88 [95% CI 1.14-3.10], p=0.01), MV (HR=2.37 [95% CI 1.38-4.07, p=0.002), and vasopressors (HR=2.21 [95% CI 1.38-3.54], p=0.001). Haploidentical transplantation did not affect outcome. Larger multicenter studies are warranted to confirm these results.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Comorbidade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Histocompatibilidade , Mortalidade Hospitalar , Humanos , Imunossupressores/uso terapêutico , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Modelos de Riscos Proporcionais , Respiração Artificial , Estudos Retrospectivos , Resultado do Tratamento , Irradiação Corporal Total
2.
Ann Biol Clin (Paris) ; 79(4): 371-378, 2021 Aug 01.
Artigo em Francês | MEDLINE | ID: mdl-34427561

RESUMO

Histocompatibility laboratories perform the biological analyses linked related to organ transplant, hematopoietic stem cells transplant, some immune dysfunction diseases and immuno-allergy after therapeutic treatment. Most of these analyses are prospectively or retrospectively performed on sera and DNA. The Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) has made some recommendations in order to define storage conditions and storage lifetime of the samples required in a histocompatibility laboratory. These recommendations have been drawn up by a working group of ten biologists. They have been established on literature review and data from method validation, which has been already performed within French laboratories (collected through a national questionnaire sent to participant laboratories). The recommendations made by the SFHI for the storage of samples for immunogenetics analyses facilitate the harmonization of practices among histocompatibility laboratories.


Assuntos
Imunogenética , Laboratórios , Bancos de Espécimes Biológicos , Histocompatibilidade , Humanos , Estudos Retrospectivos
3.
Poult Sci ; 100(9): 101335, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34329985

RESUMO

New arrangements of chicken major histocompatibility complex (MHC) class I BF and class IV BG genes are created through recombination. Characterizing the immune responses of such recombinants reveals genes or gene regions that contribute to immunity. Inbred Line UCD 003 (B17B17) served as the genetic background for congenic lines, each containing a unique MHC recombinant. After an initial cross to introduce a specific recombinant, 10 backcrosses to the inbred line produced lines with 99.9% genetic uniformity. The current study compared Rous sarcoma virus (RSV) tumor growth in 5 congenic lines homozygous for MHC recombinants (003.R1 = BF24-BG23, 003.R2 = BF2-BG23, 003.R4 = BF2-BG23, 003.R5 = BF21-BG19, and 003.R13 = BF17-BG23). Two experiments used a total of 70 birds from the 5 congenic lines inoculated with 20 pock forming units of RSV subgroup C at 6 wk of age. Tumor size was scored 6 times over 10 wk postinoculation followed by assignment of a tumor profile index (TPI) based on the tumor size scores. Tumor growth over time and rank transformed TPI values were analyzed by least squares ANOVA. Tumor size increased over the experimental period in all genotypes through 4 wk postinoculation. After this time, tumor size increased in Lines 003.R1, plateaued in Lines 003.R2, 003.R4, and 003.R13, and declined in 003.R5. Tumor growth over time was significantly lower in Line 003.R5 compared with all other genotypes. In addition, Line 003.R5 chickens had significantly lower TPI values compared with Lines 003.R2, 003.R4, and 003.R13. The TPI of Line 003.R1 did not differ significantly from any of the other genotypes. The BF21 in Line 003.R5 produced a greater response against subgroup C RSV tumors than did BF24, found in 003.R1; BF2 found in 003.R2 and R4 as well as BF17 found in 003.R13.


Assuntos
Sarcoma Aviário , Animais , Galinhas/genética , Genótipo , Histocompatibilidade , Complexo Principal de Histocompatibilidade/genética , Sarcoma Aviário/genética
4.
Front Immunol ; 12: 687254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248971

RESUMO

Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient's own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution.


Assuntos
Seleção do Doador , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Teste de Histocompatibilidade , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Rim , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/efeitos adversos , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Resultado do Tratamento
5.
Clin Transplant ; 35(9): e14406, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34180101

RESUMO

Signal-regulatory protein α (SIRPα), a polymorphic inhibitory membrane-bound receptor, and its ligand CD47 have recently been implicated in the modulation of innate immune allorecognition in murine models. Here, we investigate the potential impact of SIRPα donor-recipient mismatches on graft outcomes in human kidney transplantation. To eliminate the specific role of HLA-matching in alloresponse, we genotyped the two most common variants of SIRPα in a cohort of 55 HLA-identical, biologically-related, donor-recipient pairs. 69% of pairs were SIRPα identical. No significant differences were found between donor-recipient SIRPα-mismatch status and T cell-mediated rejection/borderline changes (25.8% vs. 25%) or slow graft function (15.8% vs. 17.6%). A trend towards more graft failure (GF) (23.5% vs. 5.3%, P = .06), interstitial inflammation (50% vs. 23%, P = .06) and significant changes in peritubular capillaritis (ptc) (25% vs. 0%, P = .02) were observed in the SIRPα-mismatched group. Unexpectedly, graft-versus-host (GVH) SIRPα-mismatched pairs exhibited higher rates of GF and tubulitis (38% vs. 5%, P = .031 and .61 ± .88 vs. 0, P = .019; respectively). Whether the higher prevalence of ptc in SIRPα-mismatched recipients and the higher rates of GF in GVH SIRPα-mismatched pairs represent a potential role for SIRPα in linking innate immunity and alloimmune rejection requires further investigation in larger cohorts.


Assuntos
Antígenos de Diferenciação/genética , Transplante de Células-Tronco Hematopoéticas , Transplante de Rim , Receptores Imunológicos/genética , Animais , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Antígenos HLA/genética , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Doadores Vivos , Camundongos
6.
Development ; 148(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34132325

RESUMO

Growing human organs in animals sounds like something from the realm of science fiction, but it may one day become a reality through a technique known as interspecies blastocyst complementation. This technique, which was originally developed to study gene function in development, involves injecting donor pluripotent stem cells into an organogenesis-disabled host embryo, allowing the donor cells to compensate for missing organs or tissues. Although interspecies blastocyst complementation has been achieved between closely related species, such as mice and rats, the situation becomes much more difficult for species that are far apart on the evolutionary tree. This is presumably because of layers of xenogeneic barriers that are a result of divergent evolution. In this Review, we discuss the current status of blastocyst complementation approaches and, in light of recent progress, elaborate on the keys to success for interspecies blastocyst complementation and organ generation.


Assuntos
Blastocisto/citologia , Quimera , Organogênese , Transplantes , Animais , Apoptose , Blastocisto/metabolismo , Diferenciação Celular , Histocompatibilidade , Humanos , Gado , Especificidade de Órgãos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Transplante Heterólogo
7.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 35(6): 769-775, 2021 Jun 15.
Artigo em Chinês | MEDLINE | ID: mdl-34142506

RESUMO

Objective: To investigate the in vivo degradation and histocompatibility of modified chitosan based on conductive composite nerve conduit, so as to provide a new scaffold material for the construction of tissue engineered nerve. Methods: The nano polypyrrole (PPy) was synthesized by microemulsion polymerization, blended with chitosan, and then formed conduit by injecting the mixed solution into a customized conduit formation model. After freeze-drying and deacidification, the nano PPy/chitosan composite conduit (CP conduit) was prepared. Then the CP conduits with different acetyl degree were resulted undergoing varying acetylation for 30, 60, and 90 minutes (CAP1, CAP2, CAP3 conduits). Fourier infrared absorption spectrum and scanning electron microscopy (SEM) were used to identify the conduits. And the conductivity was measured by four-probe conductometer. The above conduits were implanted after the subcutaneous fascial tunnels were made symmetrically on both sides of the back of 30 female Sprague Dawley rats. At 2, 4, 6, 8, 10, and 12 weeks after operation, the morphology, the microstructure, and the degradation rate were observed and measured to assess the in vivo degradation of conduits. HE staining and anti-macrophage immunofluorescence staining were performed to observe the histocompatibility in vivo. Results: The characteristic peaks of the amide Ⅱ band around 1 562 cm -1 appeared after being acetylated, indicating that the acetylation modification of chitosan was successful. There was no significant difference in conductivity between conduits ( P>0.05). SEM observation showed that the surfaces of the conduits in all groups were similar with relatively smooth surface and compact structure. After the conduits were implanted into the rats, with the extension of time, all conduits were collapsed, especially on the CAP3 conduit. All conduits had different degrees of mass loss, and the higher the degree of acetylation, the greater the mass change ( P<0.05). SEM observation showed that there were more pores at 12 weeks after implantation, and the pores showed an increasing trend as the degree of acetylation increased. Histological observation showed that there were more macrophages and lymphocytes infiltration in each group at the early stage. With the extension of implantation time, lymphocytes decreased, fibroblasts increased, and collagen fibers proliferated significantly. Conclusion: The modified chitosan basedon conductive composite nerve conduit made of nano-PPy/chitosan composite with different acetylation degrees has good biocompatibility, conductivity, and biodegradability correlated with acetylation degree in vivo, which provide a new scaffold material for the construction of tissue engineered nerve.


Assuntos
Quitosana , Animais , Feminino , Histocompatibilidade , Regeneração Nervosa , Ratos , Ratos Sprague-Dawley , Nervo Isquiático
8.
Nephrol Dial Transplant ; 36(Suppl 2): 31-36, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34153984

RESUMO

In kidney transplantation, precision medicine has already entered clinical practice. Donor and recipient human leucocyte antigen (HLA) regions are genotyped in two class 1 and usually three class 2 loci, and the individual degree of sensitization against alloimmune antigens is evaluated by the detection of anti-HLA donor-specific antibodies. Recently, the contribution of non-HLA mismatches to outcomes such as acute T- and B-cell-mediated rejection and even long-term graft survival was described. Tracking of specific alloimmune T- and B-cell clones by next generation sequencing and refinement of the immunogenicity of allo-epitopes specifically in the interaction with HLA and T- and B-cell receptors may further support individualized therapy. Although the choices of maintenance immunosuppression are rather limited, individualization can be accomplished by adjustment of dosing based on these risk predictors. Finally, supplementing histopathology by a transcriptomics analysis allows for a biological interpretation of the histological findings and avoids interobserver variability of results. In contrast to transplantation, the prescription of hemodialysis therapy is far from precise. Guidelines do not consider modifications by age, diet or many comorbid conditions. Patients with residual kidney function routinely receive the same treatment as those without. A major barrier hitherto is the definition of 'adequate' treatment based on urea removal. Kt/Vurea and related parameters neither reflect the severity of uremic symptoms nor predict long-term outcomes. Urea is poorly representative for numerous other compounds that accumulate in the body when the kidneys fail, yet clinicians prescribe treatment based on its measurement. Modern technology has provided the means to identify other solutes responsible for specific features of uremic illness and their measurement will be a necessary step in moving beyond the standardized prescription of hemodialysis.


Assuntos
Medicina de Precisão , Rejeição de Enxerto , Sobrevivência de Enxerto , Antígenos HLA/genética , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Diálise Renal
9.
Front Immunol ; 12: 687715, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177940

RESUMO

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient's personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient's humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Rejeição de Enxerto/prevenção & controle , Antígenos HLA/imunologia , Teste de Histocompatibilidade , Histocompatibilidade , Leucócitos Mononucleares/transplante , Transplante de Órgãos , Baço/imunologia , Tolerância ao Transplante , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Bases de Dados Genéticas , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Antígenos HLA/genética , Humanos , Isoanticorpos/metabolismo , Leucócitos Mononucleares/imunologia , Teste de Cultura Mista de Linfócitos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Órgãos/efeitos adversos , Fenótipo , Valor Preditivo dos Testes , Baço/metabolismo , Transcriptoma , Transplante Homólogo
10.
Front Immunol ; 12: 688301, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093594

RESUMO

The presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient's blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient's morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation.


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Dessensibilização Imunológica , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Antígenos HLA/imunologia , Histocompatibilidade , Isoanticorpos/sangue , Glicoproteínas de Membrana/antagonistas & inibidores , Transplante de Órgãos , Plasmócitos/efeitos dos fármacos , ADP-Ribosil Ciclase 1/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Animais , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Humanos , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Terapia de Alvo Molecular , Transplante de Órgãos/efeitos adversos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Fatores de Risco , Resultado do Tratamento
11.
Front Immunol ; 12: 689420, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122454

RESUMO

Long term outcomes in lung transplant are limited by the development of chronic lung allograft dysfunction (CLAD). Within the past several decades, antibody-mediated rejection (AMR) has been recognized as a risk factor for CLAD. The presence of HLA antibodies in lung transplant candidates, "sensitized patients" may predispose patients to AMR, CLAD, and higher mortality after transplant. This review will discuss issues surrounding the sensitized patient, including mechanisms of sensitization, implications within lung transplant, and management strategies.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Pulmão , Tolerância ao Transplante , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tolerância ao Transplante/efeitos dos fármacos , Resultado do Tratamento
12.
Int J Immunogenet ; 48(4): 299-316, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34109752

RESUMO

Unrelated haematopoietic stem cell transplantation (HSCT) has evolved from an experimental protocol to a potentially curative first-line treatment in a variety of haematologic malignancies. The continuous refinement of treatment protocols and supportive care paired with ongoing achievements in the technological field of histocompatibility testing enabled this transformation. Without a doubt, HLA matching is still the foremost criterion for donor selection in unrelated HSCT. However, HSCT-related treatment complications still occur frequently, often resulting in patients suffering severely or even dying as a consequence of such complications. Current literature indicates that other immune system modulating factors may play a role in the setting of HSCT. In this review, we discuss the current clinical evidence of a possible influence of nonclassical HLA antigens HLA-E, HLA-F, and HLA-G as well as the HLA-like molecules MICA and MICB, in HSCT.


Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade/imunologia , Sistema Imunitário , Antígenos HLA/classificação , Antígenos HLA-G/imunologia , Neoplasias Hematológicas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos
13.
Ann Hematol ; 100(9): 2363-2373, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33988738

RESUMO

With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6-8/8 HLA-matched unrelated donor (MUD) or 6-7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6-7/8 MRD, and 42 (36.5%) from a 6-7/8 MUD. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was higher in the 6-7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6-7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6-7/8 MUD, 6-7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6-7/8 MRD or 6-7/8 MUD is comparable to that from an 8/8 MUD.


Assuntos
Anemia Aplástica/terapia , Bussulfano/uso terapêutico , Antígenos HLA/análise , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Histocompatibilidade , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
14.
Ann Hematol ; 100(7): 1837-1847, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33948721

RESUMO

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6-7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Aloenxertos , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/efeitos adversos , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta Imunológica , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Histocompatibilidade , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Incidência , Infecções/etiologia , Infecções/mortalidade , Estimativa de Kaplan-Meier , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Linfócitos T/imunologia , Doadores não Relacionados
15.
Transplantation ; 105(6): 1317-1325, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019363

RESUMO

BACKGROUND: In March 2016, Australia's deceased donor kidney allocation program introduced calculated panel reactive antibody (cPRA) based on antibody exclusions using multiplex assays to define sensitization for waitlisted candidates. We aimed to assess the impact of this change and review access to transplantation for highly sensitized patients under the current allocation rules. METHODS: Registry data were used to reconstruct changes in panel reactive antibody (PRA)/cPRA for all patients active on the waiting list between 2013 and 2018. A multilevel, mixed-effects negative binomial regression model was used to determine the association between sensitization and transplantation rate in the cPRA era. RESULTS: Following the introduction of cPRA, there was an increase in the percentage of the waiting list classified as highly sensitized (PRA/cPRA ≥80%) from 7.2% to 27.8% and very highly sensitized (PRA/cPRA ≥99%) from 2.7% to 15.3%. Any degree of sensitization was associated with a decreased rate of transplantation with a marked reduction for those with cPRA 95%-98% (adjusted incidence rate ratio, 0.36 [95% confidence interval, 0.28-0.47], P < 0.001) and cPRA ≥99% (adjusted incidence rate ratio, 0.09 [95% confidence interval, 0.07-0.12], P < 0.001). CONCLUSIONS: The proportion of the waiting list classified as highly sensitized increased substantially following the introduction of cPRA, and despite current prioritization, very highly sensitized patients have markedly reduced access to deceased donor transplantation.


Assuntos
Antígenos HLA/imunologia , Teste de Histocompatibilidade , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Rim , Doadores de Tecidos/provisão & distribuição , Listas de Espera , Adulto , Austrália , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Acesso aos Serviços de Saúde , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
Front Immunol ; 12: 638253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936051

RESUMO

High resolution typing of the HLA-DPB1 locus for patient who requested for hematopoietic stem cell transplantation (HSCT) workup has recently become mandatory by the National Marrow Donor Program (NMDP) in order to facilitate matching between donors and recipients for better outcomes. The likelihood of identifying HLA matched donors in Hong Kong, on top of the existing HLA-A, -B, -C, and -DRB1 loci, is revisited in this study. HLA-A, -B, -C, -DRB1 and -DPB1 genotypes of 5,266 volunteer unrelated Chinese donors from the Hong Kong Bone Marrow Donor Registry (HKBMDR), were included in this study. Matching models were employed to determine the matching probabilities for 10/10(DPB1) and 9/10(DPB1) HLA match. The matching probabilities are 20% at 10/10(DPB1) HLA match and 55% at 9/10(DPB1) match, based on the existing 130,000 donors in the HKBMDR. The likelihoods of match become 27% and 65% respectively, by increasing the registry to 250,000. However, if DPB T-cell-epitope (TCE) model is considered in the matching, the probability will increase to 46% at 10/10 DPB1 permissive mismatching. Our findings provide vital information about the future planning on the targeted recruitment size, HLA typing and search strategies of the donor registry and arose the transplant physicians' acceptability to 9/10(DBP1) or 10/10(DBP1) HLA match. Nevertheless, the marrow donor registry has planned for increasing the registry size and bringing down the age of recruited donors which will ultimately enhance patient outcome.


Assuntos
Transplante de Medula Óssea , Epitopos de Linfócito T/genética , Genótipo , Cadeias beta de HLA-DP/genética , Doação Dirigida de Tecido , Frequência do Gene , Histocompatibilidade , Teste de Histocompatibilidade , Hong Kong , Humanos , Polimorfismo Genético , Sistema de Registros , Doadores de Tecidos
17.
Front Immunol ; 12: 686271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046044

RESUMO

Major advancements in the development of HLA antibody detection techniques and our understanding of the outcomes of solid organ transplant in the context of HLA antibody have occurred since the relevance of sensitization was first recognized nearly 50 years ago. Additionally, kidney paired donation programs (KPD) have become widespread, deceased donor allocation policies have changed, and several new therapeutic options have become available with promise to reduce HLA antibody. In this overview we aim to provide thoughtful guidance about when desensitization in kidney transplantation should be considered taking into account the outcomes of HLA incompatible transplantation. Novel therapeutics, desensitization endpoints, and strategies for future study will also be discussed. While most of our understanding about desensitization comes from studying kidney transplant candidates and recipients, many of the concepts discussed can be easily applied to desensitization in all of solid organ transplantation.


Assuntos
Incompatibilidade de Grupos Sanguíneos/imunologia , Dessensibilização Imunológica/métodos , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Transplante de Rim/métodos , Sistema ABO de Grupos Sanguíneos/imunologia , Doação Dirigida de Tecido , Seleção do Doador , Humanos , Doadores Vivos , Obtenção de Tecidos e Órgãos
18.
Cell Immunol ; 364: 104329, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33798908

RESUMO

Differential expression of minor histocompatibility antigens between the recipient and donor determines their disparity and can be modified by immunoproteasomes that regulate their processing and presentation. We examined the impact of HA-1 and HA-8 disparity, and immunoproteasome LMP7 polymorphism in 130 pairs. In multivariate analysis, HA-1 disparity showed a statistically significant association with an increased incidence of acute graft-versus-host disease (aGVHD) II-IV (p = 0.043, HR: 3.71, 95%CI = 1.04-13.26), while LMP7-Q/Q showed a trend toward increased incidence of aGVHD compared to LMP7-Q/K and K/K genotypes (p = 0.087, HR: 2.36, 95%CI = 0.88-6.31). All HA-1 and HA-8 disparate patients who developed aGVHD had the LMP7-Q/Q genotype. No significant association could be detected between HA-1, HA-8, or LMP7 and chronic GVHD, relapse-free survival (RFS), overall survival (OS), or transplant-related mortality (TRM). In conclusion, we suggested an association between the HA-1 disparity and the risk of developing aGVHD with a possible modifying effect of LMP7.


Assuntos
Genótipo , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Oligopeptídeos/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Doença Aguda , Adolescente , Adulto , Apresentação do Antígeno , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/mortalidade , Histocompatibilidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Complexo de Endopeptidases do Proteassoma/genética , Análise de Sobrevida , Adulto Jovem
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