ABSTRACT
Resumen: las enfermedades neurodegenerativas constituyen un problema global de salud pública que tiende a incrementarse. En la búsqueda de alternativas terapéuticas frente a estas afecciones aparecen los microquimerismos fetomaternales (células fetales en estados inmaduros de diferenciaciónadquiridas durante el embarazo) que, al tratarse de células madre, suponen una opción terapéutica similar a la terapia celular. Estudios recientes han demostrado el papel protector de los microquimerismos en la enfermedad de Alzheimer y la esclerosis múltiple; sin embargo, al tratarse de células provenientes de otro organismo surge la posibilidad de que induzcan una respuesta inmune que lleve a la aparición o potenciación de los procesos inflamatorios propios de las enfermedadesneurodegenerativas. De acuerdo con lo anterior, diversos estudios han sugerido un papel de los microquimerismos en el desarrollo de enfermedades autoinmunes. El esclarecimiento de las características, funciones, vías de ingreso, localización e interacciones de los microquimerismos con el sistema inmune del organismo hospedero es relevante en la medida en que pueden guiar el desarrollode tratamientos frente a este tipo de enfermedades. En esta revisión se describen algunos de estos aspectos relevantes.
Abstract: neurodegenerative diseases represent a major and increasing public health problem around the world. In the search for therapeutic alternatives against these conditions, feto-maternal microchimerisms (immature fetal cells acquired during pregnancy) appear as a possible therapeutic option similar to stem cell therapy. In fact, several studies have found that the microchimerisms play a protective role against Alzheimer´s disease and multiple sclerosis. Nonetheless, given the fact that the microchimerisms are ®foreign cells¼, they could induce an immune response, leading to the apparition or exacerbation of the inflammatory responses characteristic of neurodegenerative diseases.According to this, several studies have suggested a role for microchimerisms in the development of autoimmune diseases. The elucidation of characteristics, functions, ways of acquisition, paths of entry, localization, and interactions between microchimerisms and the immune system of the host can serve as a guide towards the development of a treatement against these disease. In this review, some of these important aspects are described.
Subject(s)
Humans , Alzheimer Disease , Frontotemporal Dementia , Major Histocompatibility Complex , Neurodegenerative DiseasesABSTRACT
BACKGROUND: Bidirectional traffic of cells at the feto-maternal interface has been shown during pregnancy and fetal cells have been found to persist in maternal peripheral blood for decades after childbirth. Fetal-microchimerism has been reported in women with scleroderma, which shares a number of characteristics with chronic graft versus host disease (GVHD), although its contribution to the disease pathogenesis remains unclear. We performed this study to determine the frequency of male microchimerism in peripheral blood of patients with scleroderma or normal healthy women with son.METHODS: PCR targeting the Y chromosome specific DYZ1 sequence was employed to test DNA extracted from peripheral blood mononuclear cells of 26 women with scleroderma and 10 healthy women who had given birth to at least one son.RESULTS: Male DNA was detected in 16 of 26 (61.5%) women with scleroderma. Whereas male DNA was not detected in any healthy women who had given birth to son.CONCLUSION: Although fetal microchimerism in women with scleroderma was documented, additional studies will be necessary to determine whether microchimerism plays a role in the pathogenesis of this or other autoimmune disease.
Subject(s)
Female , Humans , Male , Pregnancy , Autoimmune Diseases , Chimerism , DNA , Graft vs Host Disease , Parturition , Polymerase Chain Reaction , Skin , Skin Manifestations , Transplants , Y ChromosomeABSTRACT
BACKGROUND: Bidirectional traffic of cells at the feto-maternal interface has been shown during pregnancy and fetal cells have been found to persist in maternal peripheral blood for decades after childbirth. Fetal-microchimerism has been reported in women with scleroderma, which shares a number of characteristics with chronic graft versus host disease (GVHD), although its contribution to the disease pathogenesis remains unclear. We performed this study to determine the frequency of male microchimerism in peripheral blood of patients with scleroderma or normal healthy women with son. METHODS: PCR targeting the Y chromosome specific DYZ1 sequence was employed to test DNA extracted from peripheral blood mononuclear cells of 26 women with scleroderma and 10 healthy women who had given birth to at least one son. RESULTS: Male DNA was detected in 16 of 26 (61.5%) women with scleroderma. Whereas male DNA was not detected in any healthy women who had given birth to son. CONCLUSION: Although fetal microchimerism in women with scleroderma was documented, additional studies will be necessary to determine whether microchimerism plays a role in the pathogenesis of this or other autoimmune disease.
Subject(s)
Female , Humans , Male , Pregnancy , Autoimmune Diseases , Chimerism , DNA , Graft vs Host Disease , Parturition , Polymerase Chain Reaction , Skin , Skin Manifestations , Transplants , Y ChromosomeABSTRACT
El microquimerismo humano se define como la presencia dentro de un individuo de una pequeña población de células originadas en un individuo genéticamente distinto. El microquimerismo adquirido de forma natural se desarrolla a lo largo del embarazo, como una consecuencia del ampliamente demostrado tráfico bidireccional transplacentario de células. Esta trasferencia resulta en un estado microquimérico a décadas posparto, tanto para la madre (microquimerismo fetal) como para su progenie (microquimerismo materno). Aún más, el establecimiento de esta condición ocurre, iatrogénicamente, posterior al transplante de órganos y la transfusión de sangre. Actualmente el microquimerismo es un tema de gran interés alrededor del mundo, dadas sus múltiples posibles implicaciones en la salud y en la enfermedad. Su estudio comenzó a raíz del potencial para el desarrollo de técnicas de diagnóstico prenatal no invasivo, en le presente se tienen amplias expectativas de su utilidad en la terapia con células madre. Se ha propuesto que el microquimerismo podría estar implicado en la patogénesis de ciertas enfermedades autoinmunes, en la preparación de tejidos, el cáncer y la inducción de tolerancia...
Subject(s)
Humans , Autoimmune Diseases , Cell Compartmentation , Cell Movement , Genome, Human , Placenta , Prenatal Diagnosis , Stem Cells , Costa RicaABSTRACT
Remarkable achievements have been made for lymphocyte infusion of lymphoma and leukemia, especially of lymphoproliferative disease within twenty-first century. The donor lymphocyte infusion or mobilized donor lymphocyte infusion (DLI/DSI) offer an opportunity of second remission for relapse patients post-transplantation. Cytokine-induced killer/DC cytokine-induced killer play an anti-tumor activity beyond non-MHC restricted. Cytotoxic lymphocyte infusion activated by synthetic tumor antigen produces targeted effects of anti-tumor. Transgenic CTL of anti-tumor TCR has brought the dawn in lymphoma and leukemia patients with defective lymphocytes. Maternal lymphocyte infusion play an anti-tumor/viral activity by avoiding the immune barrier of HLA mismatch.
ABSTRACT
El quimerismo genético un concepto no bien esclarecido en la comunidad científica, aún confundido con mosaicismo. En la presente revisión pretendemos definirlo con un enfoque legal y ejemplificarlo con una serie de casos descritos en la literatura médica, los cuales nos orientan a la diferencia clara entre mosaicismo y quimerismo. Dentro de esta serie separamos los casos que se relacionan con hermafroditismo y los no relacionados. Además, hacemos referencia a un nuevo concepto que genera polémica en la investigación, el microquimerismo, relacionado con transfusiones sanguíneas, transplantes y la génesis de las enfermedades autoinmunes.
Genetic chimerism is a not well defined concept among the scientific community; it is still confused with mosaicism. In the following review we intend to define the concept with a legal point of view and exemplify it with a series of cases described in medical texts. The cases lead us to find the clear difference between mosaicism and chimerism. Contained in these series of cases we have separated the ones related with hemaphroditism from the ones that are not related. We also make reference to a new concept that generates controversy in the investigation; microchimerism, which is related with blood transfusions, transplants and genesis of autoimmune diseases..
Subject(s)
Humans , Disorders of Sex Development , Sex Chromosome Disorders/pathology , Chimerism , Jurisprudence , Mosaicism , Costa Rica , Forensic MedicineABSTRACT
Objective To study the effect of feto-matemal microchimerism in the treatment of activated human leukocyte antigen (HLA) haploidentical mobilized peripheral blood cells against solid tumors. Methods Genomic DNA samples of 25 pairs of HLA haploidentical donors and recipients were extracted. The donor-derived HLA-DRB loci were detected with nested PCR-sequence specific primer(SSP) typing. The mixed lymphocyte proliferation action between the patients and respective donors, the engraftment of donor's cells and the serum levels of Th1/Th2 type of cytokines were measured with MTT,FISH and EIJSA method respectively. The survival time of patients with or without feto-matemal microchimerism were compared as well. Results Using nested PCR-SSP typing, the positive rates of feto-maternal microchimerism in the 25 pairs of HLA haploidentical donors and recipients were 40% in the maternal/children pairs and 0 in the paternal/children pairs. The chimerism positive patients showed less proliferation activity when cocultured with respective donors as compared with unrelated ones (P=0.03).Only one chimerism positive patient experienced the engraft of donor's cell 3 months after treatment as the donor derived XX chromosome was identified with FISH. When the data of chimerism positive patients were deleted, the serum levels of IFNγ 1 month after treatment dropped dramatically from 171.4 (26. 3～258.4) ng/L to 29. 4(1.2～39.9)ng/L. The survival time in chimerism positive patients of the maternal/children pairs was significantly longer than that in chimerism negative patients, which was (31.2±4. 3) months and (11.1±3.3) months, respectively (P=0.036). Conclusion Feto-maternal microchimerism might induce anergy in the HLA haploidentical donors, favor the engraftment of donor's progenitors and maintenance of positive microenvironment and prolong the survival time.
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BACKGROUND: Microchimerism detected after solid organ transplatnation has been reported to be associated with improved graft survival with some controversies. However, the effect of pretransplantation microchimerism on the graft survival has not been studied to date. The aim of this study was to investigate the effect of pretransplantation fetomaternal microchimerism on the graft survival in renal transplantation. METHODS: A total of 27 cases of renal transplantation performed between mother and child pairs during the period from 1996 to 2004 at the Seoul National University Hospital were studied retrospectively. Presence of pretransplantation fetomaternal microchimerism was detected using DNA samples extracted from peripheral blood collected before the operation. Microchimerism for the HLA-DRB1 gene of non-inherited maternal antigen was detected using nested PCR-single strand conformation polymorphism (SSCP) method. The function and survival of allograft was compared between the groups with and without microchimerism. RESULTS: Microchimerism was detected in 10 (37%) of the 27 cases. In the group with microchimerism, serum creatinine levels at one and three years after transplantation tended to be lower in the patients with microchimerism than in those without microchimerism (one year, 1.1 vs 1.3 mg/dL, P=0.133; three years, 1.2 vs 1.5 mg/dL, P=0.083). The rejection free survival tended to be longer in the patients with microchimerism than in those without microchimerism (113.5 vs 72.5 months, P=0.146). CONCLUSIONS: This study was limited by small number of cases, and an extended study on a larger number of patients is needed to clarify the role of pretransplantation fetomaternal microchimerism on allograft survival.
Subject(s)
Child , Humans , Chimerism , Creatinine , DNA , Graft Survival , HLA-DRB1 Chains , Kidney Transplantation , Mothers , Rejection, Psychology , Retrospective Studies , Transplantation, Homologous , TransplantsABSTRACT
OBJECTIVE: To investigate whether fetal microchimeric cells were detected in ovarian tissues with pelvic endometriosis. METHODS: Ovarian tissues with endometriosis were obtained from five women who had at least one live-born son and who underwent enucleation of endometriotic cyst or oophorectomy after a diagnosis of endometriotic cyst. Control tissues were obtained from five women with endometriosis who had no pregnant history. Tissue sections were analyzed with fluorescence in situ hybridization for the presence of fetal cells, defined by X and Y chromosome. RESULTS: Fluorescence in situ hybridization using paraffin-embedded ovarian specimens was performed successfully. Male cells were found in ovarian tissues from all five patients. No male cells were found in ovarian tissues from all five controls. CONCLUSION: Fetal microchimeric cells, possibly from feto-maternal cell trafficking were detected in ovarian tissues with endometriosis were obtained from women who had prior male pregnancies. Further study is necessary to understand the role of persistent fetal microchimeric cells in the progression of endometriosis.
Subject(s)
Female , Humans , Male , Pregnancy , Chimerism , Diagnosis , Endometriosis , Fluorescence , In Situ Hybridization , Ovariectomy , Y ChromosomeABSTRACT
PURPOSE: This project is designed to investigate the immune response of a rat transplantation model to donor specific allogeneic blood transfusion (DST) prior to kidney transplantation. It has been hypothesized that partial activation of the immune system due to allogeneic antigen presentation, followed by immune unresponsiveness. In addition, previous models have shown prolonged donor cell microchimerism can be established following organ transplantation. Mixed chimerism has been demonstrated in organ transplant recipients surviving over a long period. Attempts were made to assess the fate and movements of donor cells following organ transplantation. METHODS: Rat male-to-female renal transplantation and microchimerism was assessed by semiquantitative PCR. A PCR specific for the Y-chromosome (sex-determining region Y[Sry]) allowed the distinction of small amounts of male cells in a large excess of female cells. The study group was divided into four according to the donor specific transfusion (DST) and cyclosporin (CsA) Group 1 are recipients without DST or CsA administration, Group 2 are recipient with CsA, Group 3 with DSILT and Group 4 with full immunosuppresive agent (CsA & DSILT). The samples were obtained at thymus, lymph node, spleen and sternum following transplantation day 1, 7, 21. Donor cell microchimerism were detected by donor Y chromosome in female recipients using PCR RESULTS: The Y-chromosome was detected at high levels in group 4, 21 days after transplantation. The detection ratio in the lymph node was higher than in the other organs. CONCLUSION: The fate of donor cell were closely related to he additional supporting immunosuppressive agent.
Subject(s)
Animals , Female , Humans , Male , Rats , Antigen Presentation , Blood Transfusion , Chimerism , Cyclosporine , Immune System , Kidney Transplantation , Kidney , Leukocytes , Lymph Nodes , Organ Transplantation , Polymerase Chain Reaction , Spleen , Sternum , Thymus Gland , Tissue Donors , Transplants , Y ChromosomeABSTRACT
Objective To investigate the status of microchimerism in recipients and the relation between microchimerism and immunologic tolerance after vascularized allograft bone transplantation. Methods X-ray and histological examinations were performed on recipients after massive vascularized shaft of femur from female Japanese white rabbit donors was transplanted to male recipients. Microchimerism in different organs and tissues were checked postoperatively using a semi-quantitative polymerase chain reaction (PCR) with a Y-chromosome specific primer at different time. Results X-ray and histological examinations showed typical bone union in the experiment group but irregular new bone calluses surrounded the transplanted bones, with high density sequestrum in the control group.Semiquantitative PCR with a Y-chyomosome specific primer indicated that the incidence of microchimerism in organs and tissues in the experiment group was higher than that in the control group postoperatively and increased with time. Conclusions After vascularized allograft bone transplantation, organs and tissues show microchimerism that has a positive correlation with the histocompatibility of the transplanted bones.
ABSTRACT
BACKGROUND: Immune tolerance is regarded as the goal of the organ transplantation (TPLx), but the mechanism of tolerance induction remains to be established. Microchimerism (MC) development in long-surviving recipients after solid organ TPLx might be linked to tolerance. OBJECTIVE: We investigated the development and clinical relevance of donor specific MC in living related renal transplants with good graft function more than 3 years after TPLx. The relationship between MC and mixed lymphocyte reaction (MLR) hyporeactivity was also evaluated. MATERIALS AND METHODS: Eighteen recipients were included in this study among recipients whose renal function were stable for more than 3 years and have at least one mismatch of HLA DR loci. Donor-specific MC was examined with nested PCR method using HLA DRB1 gene probe in DNA extracted from peripheral blood and forearm skin tissue samples. Mean age at TPLx was 28.9 yrs (range: 13~42 yrs) and mean follow-up period was 67.4 months (range: 36~173 mos). Male to female ratio was 11:7. Acute rejection occurred in 4 and were reversed with steroid pulse therapy. All donors were alive (parent:8, sibling:9, offspring:1). Immunosuppression regimens were CSA(+)PDS in 11, AZA PDS in 1, AZA CSA(+)PDS in 5, and CSA monotherapy in 1. Mean serum BUN/Cr at the point of this study were 22.2+/-6.7 / 1.54+/-0.81 (mg/dL). The sensitivity of nested PCR using HLA DRB1 probe was 1/105~1/106. RESULTS: Donor-specific MC was detected in 6 (33.3%) (5 in blood, 5 in skin tissue). Nested PCR method was more sensitive than single round SSP-PCR method which showed only 2 positive recipients (11.1%). Two of four acute rejection experienced recipients were MC positive. Recipients were divided into two groups according to the follow-up period of 5 years. Two groups showed equal number of MC positivity. MLR was decreased in a group of more than 5 yrs follow-up. However, there was no difference in the decrement of MLR between MC positive and negative groups. CONCLUSION: MC was detected in 33.3% patients with nested PCR method. Since the MC positivity and MLR hyporesponsiveness shows no relationship, the significance of MC relevant to tolerance is to be determined through further study.
Subject(s)
Female , Humans , Male , Chimerism , DNA , Follow-Up Studies , Forearm , HLA-DRB1 Chains , Immune Tolerance , Immunosuppression Therapy , Kidney Transplantation , Lymphocyte Culture Test, Mixed , Organ Transplantation , Polymerase Chain Reaction , Skin , Tissue Donors , TransplantsABSTRACT
BACKGROUND: Immune tolerance is regarded as the goal of the organ transplantation (TPLx), but the mechanism of tolerance induction remains to be established. Microchimerism (MC) development in long-surviving recipients after solid organ TPLx might be linked to tolerance. OBJECTIVE: We investigated the development and clinical relevance of donor specific MC in living related renal transplants with good graft function more than 3 years after TPLx. The relationship between MC and mixed lymphocyte reaction (MLR) hyporeactivity was also evaluated. MATERIALS AND METHODS: Eighteen recipients were included in this study among recipients whose renal function were stable for more than 3 years and have at least one mismatch of HLA DR loci. Donor-specific MC was examined with nested PCR method using HLA DRB1 gene probe in DNA extracted from peripheral blood and forearm skin tissue samples. Mean age at TPLx was 28.9 yrs (range: 13~42 yrs) and mean follow-up period was 67.4 months (range: 36~173 mos). Male to female ratio was 11:7. Acute rejection occurred in 4 and were reversed with steroid pulse therapy. All donors were alive (parent:8, sibling:9, offspring:1). Immunosuppression regimens were CSA(+)PDS in 11, AZA PDS in 1, AZA CSA(+)PDS in 5, and CSA monotherapy in 1. Mean serum BUN/Cr at the point of this study were 22.2+/-6.7 / 1.54+/-0.81 (mg/dL). The sensitivity of nested PCR using HLA DRB1 probe was 1/105~1/106. RESULTS: Donor-specific MC was detected in 6 (33.3%) (5 in blood, 5 in skin tissue). Nested PCR method was more sensitive than single round SSP-PCR method which showed only 2 positive recipients (11.1%). Two of four acute rejection experienced recipients were MC positive. Recipients were divided into two groups according to the follow-up period of 5 years. Two groups showed equal number of MC positivity. MLR was decreased in a group of more than 5 yrs follow-up. However, there was no difference in the decrement of MLR between MC positive and negative groups. CONCLUSION: MC was detected in 33.3% patients with nested PCR method. Since the MC positivity and MLR hyporesponsiveness shows no relationship, the significance of MC relevant to tolerance is to be determined through further study.
Subject(s)
Female , Humans , Male , Chimerism , DNA , Follow-Up Studies , Forearm , HLA-DRB1 Chains , Immune Tolerance , Immunosuppression Therapy , Kidney Transplantation , Lymphocyte Culture Test, Mixed , Organ Transplantation , Polymerase Chain Reaction , Skin , Tissue Donors , TransplantsABSTRACT
Objective:To examine whether the existence of the donor-and-recipient-derived DNA chimerism in recipient’s plasma can be a predictive marker for the status of transplanted organ.Methods:One hundred and twenty-six female patients who had been transplanted with male kidney were enrolled in the present study.In these female recipients,the SRY1,DYZ11st and DYZ12nd genes on the Y chromosome from the plasma were prospectively examined using reverse transcription polymerase chain reaction (RT-PCR).Results:SRY1,DYZ11st and DYZ12nd sequences were detected in the cell-free blood (plasma) of 97 (77%) of 126 female patients with male kidney.The average time-span when the transplanted kidneys functioned was 8.7 years and 5.4 years among microchimerism-positive and microchimerism-negative recipients,respectively.The frequency of the patients who had acute rejection after renal transplantation was approximately 10% and 28%in microchimerism-positive and microchimerism-negative recipients,respectively.Serum creatinine levels in microchimerism-positive patients were significantly lower than those in microchimerism-negative patients.Conclusion:These results suggest that plasma DNA microchimerism is present in certain patients following renal transplantation and measurement of plasma DNA microchimerism using quantitative RT-PCR might be a useful predictor for the acceptance of transplanted kidneys.
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Objective To explore the influence of the fetal microchemirism in the thyroid tissue on the Graves' disease(GD) animal model.Methods Mice in experimental group were injected with Ad-TSH289(5?108IU) to construct the GD animal model,and when the immunization was over,the experimental group was randomly divided into three parts again: two groups were mated with male mice until two weeks of pregnancy or two weeks post-partum while the other group was simple immunized with Ad-TSH289 only.SRY was tested by real-time PCR.Thyroid tissue was stained with HE for pathological examination.Results Histological examination of the thyroid gland revealed that 61.8% of simple immunized mice had goiter,the success rate of GD animal model was 38.5% in pregnancy group,but 76.9% in postpartum groups(P