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M. Louise Markert - One of the best experts on this subject based on the ideXlab platform.
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Cultured Thymus Tissue transplantation
Stiehm's Immune Deficiencies, 2020Co-Authors: M. Louise Markert, Elizabeth A. Mccarthy, Stephanie E. Gupton, Allison Pecha LimAbstract:Abstract Transplantation of thymic Tissue was initially attempted in the 1960s and 1970s. Long-term successes were rare but these studies served as an important foundation. Today, cultured Thymus Tissue transplantation (CTTT) is performed for athymic infants. Almost all CTTT recipients are infants with complete DiGeorge anomaly. CTTT is an investigational product regulated by the FDA. Duke is only center in the United States performing Thymus transplantation and this chapter reviews the experience to date.
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Chapter 60 – Thymus Transplantation
Stiehm's Immune Deficiencies, 2014Co-Authors: M. Louise MarkertAbstract:Thymus transplantation is an experimental procedure in which allogeneic, cultured, postnatal Thymus Tissue is transplanted into an athymic infant. Almost all transplant recipients are infants with complete DiGeorge anomaly. The donor Thymus is obtained as discarded Tissue from pediatric heart surgery after informed consent. It is sectioned, and maintained in culture while donor screening is performed. After 2–3 weeks in culture, the Thymus Tissue is transplanted into the quadriceps muscle of the athymic infant under general anesthesia in the operating room. Temporary immunosuppression is required in approximately half of transplant recipients. In a series of 67 consecutive patients, the 1-year survival rate was 76%. The median age of survivors is 7.8 years. Naive CD4+ and CD8+ T cells develop over the first 6–9 months. Immunosuppression, immunoglobulin replacement therapy, and Pneumocystis prophylaxis are discontinued at approximately 1 year post-transplantation.
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Characterization of cultured Thymus Tissue used for transplantation with emphasis on promiscuous expression of thyroid Tissue-specific genes.
Immunologic Research, 2008Co-Authors: Chia-san Hsieh, Laura P. Hale, Blythe H. Devlin, M. Louise MarkertAbstract:Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after Thymus transplantation. This study was designed to assess the effect of culture of Thymus Tissue on the expression of genes involved in the development of autoimmunity. The expression of autoimmune regulator (AIRE), thyroglobulin (TG), thyroid peroxidase (TPO), and cytokeratin RNAs was examined in thymocytes and Thymus Tissue on the day of Thymus harvest and after 14 and 21 days of culture. Immunohistochemistry was used to evaluate the cytokeratin expression in the Thymus Tissue. AIRE, TG, TPO, and cytokeratin mRNAs were found in harvest-day, 14-day and 21-day cultured Tissues. Levels of AIRE, TG, and cytokeratin mRNAs were mostly higher after culture compared to expression on the harvest day, likely secondary to thymocyte depletion.
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Factors affecting success of Thymus transplantation for complete DiGeorge anomaly
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2008Co-Authors: M. Louise Markert, Blythe H. Devlin, Ivan K. Chinn, Elizabeth A. MccarthyAbstract:Thymus transplantation shows promise for the treatment of athymia in complete DiGeorge anomaly. This report reviews the effects of dose of Thymus Tissue, ABO compatibility, HLA matching, culture conditions, age of donor and immunosuppression of recipient on immune outcomes at 1 year after transplantation. Forty-nine athymic subjects have been treated with cultured postnatal allogeneic Thymus Tissue; 36 (73%) survive with only one subject on immunosuppression at 1.5 years. Of 31 surviving subjects more than 1 year after transplantation, 30 (97%) developed naive T cells, T-cell proliferative responses to mitogens and a diverse T-cell receptor beta variable (TCRBV) repertoire. The dose of Thymus Tissue, HLA matching and use of immunosuppression had nonsignificant effects on these outcome variables. Removal of deoxyguanosine from culture medium and length of culture did not adversely affect outcomes. Use of Thymus Tissue from donors over 1 month of age, versus under 1 month, resulted in higher total T-cell numbers (p = 0.03). However, this finding must be confirmed in a prospective trial. Although subtle immune effects may yet be associated with some of the factors tested, it is remarkable that consistently good immune outcomes result despite variation in dose, HLA matching and use of immunosuppression.
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Use of Allograft Biopsies to Assess Thymopoiesis after Thymus Transplantation
Journal of immunology (Baltimore Md. : 1950), 2008Co-Authors: M. Louise Markert, Blythe H. Devlin, Jeffrey C. Hoehner, Henry E. Rice, Michael A. Skinner, Laura P. HaleAbstract:Thymus allograft biopsies were performed in athymic infants with complete DiGeorge anomaly after Thymus transplantation to assess whether the Thymus allograft Tissue was able to support thymopoiesis. Forty-four consecutive infants were treated with postnatal cultured Thymus allografts. Thirty biopsies and six autopsies evaluating the allograft site were obtained in 33 infants, 23 of whom survive. The allograft was examined by immunohistochemistry for evidence of thymopoiesis. Grafted Thymus Tissue was found in 25 of 30 biopsies, 23 of which showed thymopoiesis. All 19 survivors with thymopoiesis on biopsy developed naive T cells and T cell function. Autopsies were done in six subjects, three of whom had biopsies. All autopsy samples contained Thymus Tissue including one for which the biopsy had not contained graft. Of the six autopsies, one had evidence of thymopoiesis. Epithelium without thymopoiesis was seen in two of 25 biopsies in which Thymus Tissue was detected and in five of six autopsies. Graft rejection was seen in one autopsy. Biopsies were important for showing the following: 1) the damaging effect of pulse steroids on thymopoiesis; 2) the need for adequate immunosuppression of atypical subjects; and 3) the presence of thymopoiesis in the presence of ongoing immunosuppression. In addition, the biopsy could rule out graft rejection in the atypical subjects who had oligoclonal T cells that could cause rejection. In summary, combining biopsy and autopsy data, allogeneic Thymus Tissues showed thymopoiesis in 24 of 29 (86%) evaluable transplants. The results of these biopsies led to improved care of these complex patients.
Blythe H. Devlin - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of tolerance to parental parathyroid Tissue when combined with human allogeneic Thymus transplantation
The Journal of Allergy and Clinical Immunology, 2010Co-Authors: Ivan K. Chinn, Elizabeth A. Mccarthy, Stephanie E. Gupton, Michael A. Skinner, John A Olson, Dongfeng Chen, Francisco A Bonilla, Robert L Roberts, Maria Kanariou, Blythe H. DevlinAbstract:Background The induction of tolerance toward third-party solid organ grafts with allogeneic Thymus Tissue transplantation has not been previously demonstrated in human subjects. Objective Infants with complete DiGeorge anomaly (having neither Thymus nor parathyroid function) were studied for conditions and mechanisms required for the development of tolerance to third-party solid organ Tissues. Methods Four infants who met the criteria received parental parathyroid with allogeneic Thymus transplantation and were studied. Results Two of 3 survivors showed function of both grafts but subsequently lost parathyroid function. They demonstrated alloreactivity against the parathyroid donor in mixed lymphocyte cultures. For these 2 recipients, parathyroid donor HLA class II alleles were mismatched with the recipient and Thymus. MHC class II tetramers confirmed the presence of recipient CD4 + T cells with specificity toward a mismatched parathyroid donor class II allele. The third survivor has persistent graft function and lacks alloreactivity toward the parathyroid donor. All parathyroid donor class II alleles were shared with either the recipient or the Thymus graft, with minor differences between the parathyroid (HLA-DRB1∗1104) and Thymus (HLA-DRB1∗1101). Tetramer analyses detected recipient T cells specific for the parathyroid HLA-DRB1∗1104 allele. Alloreactivity toward the parathyroid donor was restored with low doses of IL-2. Conclusion Tolerance toward parathyroid grafts in combined parental parathyroid and allogeneic Thymus transplantation requires matching of Thymus Tissue to parathyroid HLA class II alleles to promote negative selection and suppression of recipient T cells that have alloreactivity toward the parathyroid grafts. This matching strategy may be applied toward tolerance induction in future combined Thymus and solid organ transplantation efforts.
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Characterization of cultured Thymus Tissue used for transplantation with emphasis on promiscuous expression of thyroid Tissue-specific genes.
Immunologic Research, 2008Co-Authors: Chia-san Hsieh, Laura P. Hale, Blythe H. Devlin, M. Louise MarkertAbstract:Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after Thymus transplantation. This study was designed to assess the effect of culture of Thymus Tissue on the expression of genes involved in the development of autoimmunity. The expression of autoimmune regulator (AIRE), thyroglobulin (TG), thyroid peroxidase (TPO), and cytokeratin RNAs was examined in thymocytes and Thymus Tissue on the day of Thymus harvest and after 14 and 21 days of culture. Immunohistochemistry was used to evaluate the cytokeratin expression in the Thymus Tissue. AIRE, TG, TPO, and cytokeratin mRNAs were found in harvest-day, 14-day and 21-day cultured Tissues. Levels of AIRE, TG, and cytokeratin mRNAs were mostly higher after culture compared to expression on the harvest day, likely secondary to thymocyte depletion.
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Factors affecting success of Thymus transplantation for complete DiGeorge anomaly
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2008Co-Authors: M. Louise Markert, Blythe H. Devlin, Ivan K. Chinn, Elizabeth A. MccarthyAbstract:Thymus transplantation shows promise for the treatment of athymia in complete DiGeorge anomaly. This report reviews the effects of dose of Thymus Tissue, ABO compatibility, HLA matching, culture conditions, age of donor and immunosuppression of recipient on immune outcomes at 1 year after transplantation. Forty-nine athymic subjects have been treated with cultured postnatal allogeneic Thymus Tissue; 36 (73%) survive with only one subject on immunosuppression at 1.5 years. Of 31 surviving subjects more than 1 year after transplantation, 30 (97%) developed naive T cells, T-cell proliferative responses to mitogens and a diverse T-cell receptor beta variable (TCRBV) repertoire. The dose of Thymus Tissue, HLA matching and use of immunosuppression had nonsignificant effects on these outcome variables. Removal of deoxyguanosine from culture medium and length of culture did not adversely affect outcomes. Use of Thymus Tissue from donors over 1 month of age, versus under 1 month, resulted in higher total T-cell numbers (p = 0.03). However, this finding must be confirmed in a prospective trial. Although subtle immune effects may yet be associated with some of the factors tested, it is remarkable that consistently good immune outcomes result despite variation in dose, HLA matching and use of immunosuppression.
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Use of Allograft Biopsies to Assess Thymopoiesis after Thymus Transplantation
Journal of immunology (Baltimore Md. : 1950), 2008Co-Authors: M. Louise Markert, Blythe H. Devlin, Jeffrey C. Hoehner, Henry E. Rice, Michael A. Skinner, Laura P. HaleAbstract:Thymus allograft biopsies were performed in athymic infants with complete DiGeorge anomaly after Thymus transplantation to assess whether the Thymus allograft Tissue was able to support thymopoiesis. Forty-four consecutive infants were treated with postnatal cultured Thymus allografts. Thirty biopsies and six autopsies evaluating the allograft site were obtained in 33 infants, 23 of whom survive. The allograft was examined by immunohistochemistry for evidence of thymopoiesis. Grafted Thymus Tissue was found in 25 of 30 biopsies, 23 of which showed thymopoiesis. All 19 survivors with thymopoiesis on biopsy developed naive T cells and T cell function. Autopsies were done in six subjects, three of whom had biopsies. All autopsy samples contained Thymus Tissue including one for which the biopsy had not contained graft. Of the six autopsies, one had evidence of thymopoiesis. Epithelium without thymopoiesis was seen in two of 25 biopsies in which Thymus Tissue was detected and in five of six autopsies. Graft rejection was seen in one autopsy. Biopsies were important for showing the following: 1) the damaging effect of pulse steroids on thymopoiesis; 2) the need for adequate immunosuppression of atypical subjects; and 3) the presence of thymopoiesis in the presence of ongoing immunosuppression. In addition, the biopsy could rule out graft rejection in the atypical subjects who had oligoclonal T cells that could cause rejection. In summary, combining biopsy and autopsy data, allogeneic Thymus Tissues showed thymopoiesis in 24 of 29 (86%) evaluable transplants. The results of these biopsies led to improved care of these complex patients.
Lewis E. Braverman - One of the best experts on this subject based on the ideXlab platform.
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Thymic Uptake of Iodine-131 in the Anterior Mediastinum
The Journal of Nuclear Medicine, 1996Co-Authors: Irini E. Veronikis, Peter H. Simkin, Lewis E. BravermanAbstract:Two thyroidectomized patients with a history of differentiated thyroid carcinoma are presented who had nonmetastatic mediastinal 131 I uptake following therapeutic doses of 131 I. Chest CT scans in both patients demonstrated an anterior mediastinal mass. Surgical excision in one patient and a percutaneous CT-guided fine needle aspiration biopsy in the other disclosed normal Thymus Tissue. Iodine-131 uptake in the anterior mediastinum in patients thyroidectomized for follicular or papillary thyroid carcinoma may represent the Thymus.
Laura P. Hale - One of the best experts on this subject based on the ideXlab platform.
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Characterization of cultured Thymus Tissue used for transplantation with emphasis on promiscuous expression of thyroid Tissue-specific genes.
Immunologic Research, 2008Co-Authors: Chia-san Hsieh, Laura P. Hale, Blythe H. Devlin, M. Louise MarkertAbstract:Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after Thymus transplantation. This study was designed to assess the effect of culture of Thymus Tissue on the expression of genes involved in the development of autoimmunity. The expression of autoimmune regulator (AIRE), thyroglobulin (TG), thyroid peroxidase (TPO), and cytokeratin RNAs was examined in thymocytes and Thymus Tissue on the day of Thymus harvest and after 14 and 21 days of culture. Immunohistochemistry was used to evaluate the cytokeratin expression in the Thymus Tissue. AIRE, TG, TPO, and cytokeratin mRNAs were found in harvest-day, 14-day and 21-day cultured Tissues. Levels of AIRE, TG, and cytokeratin mRNAs were mostly higher after culture compared to expression on the harvest day, likely secondary to thymocyte depletion.
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Use of Allograft Biopsies to Assess Thymopoiesis after Thymus Transplantation
Journal of immunology (Baltimore Md. : 1950), 2008Co-Authors: M. Louise Markert, Blythe H. Devlin, Jeffrey C. Hoehner, Henry E. Rice, Michael A. Skinner, Laura P. HaleAbstract:Thymus allograft biopsies were performed in athymic infants with complete DiGeorge anomaly after Thymus transplantation to assess whether the Thymus allograft Tissue was able to support thymopoiesis. Forty-four consecutive infants were treated with postnatal cultured Thymus allografts. Thirty biopsies and six autopsies evaluating the allograft site were obtained in 33 infants, 23 of whom survive. The allograft was examined by immunohistochemistry for evidence of thymopoiesis. Grafted Thymus Tissue was found in 25 of 30 biopsies, 23 of which showed thymopoiesis. All 19 survivors with thymopoiesis on biopsy developed naive T cells and T cell function. Autopsies were done in six subjects, three of whom had biopsies. All autopsy samples contained Thymus Tissue including one for which the biopsy had not contained graft. Of the six autopsies, one had evidence of thymopoiesis. Epithelium without thymopoiesis was seen in two of 25 biopsies in which Thymus Tissue was detected and in five of six autopsies. Graft rejection was seen in one autopsy. Biopsies were important for showing the following: 1) the damaging effect of pulse steroids on thymopoiesis; 2) the need for adequate immunosuppression of atypical subjects; and 3) the presence of thymopoiesis in the presence of ongoing immunosuppression. In addition, the biopsy could rule out graft rejection in the atypical subjects who had oligoclonal T cells that could cause rejection. In summary, combining biopsy and autopsy data, allogeneic Thymus Tissues showed thymopoiesis in 24 of 29 (86%) evaluable transplants. The results of these biopsies led to improved care of these complex patients.
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Transplantation of Thymus Tissue in Complete DiGeorge Syndrome
The New England journal of medicine, 1999Co-Authors: M. Louise Markert, Andreas Boeck, Laura P. Hale, Amy Kloster, Tanya M. Mclaughlin, Milena N. Batchvarova, Daniel C. Douek, Richard A. Koup, Donna D. Kostyu, Frances E. WardAbstract:Background The DiGeorge syndrome is a congenital disorder that affects the heart, parathyroid glands, and Thymus. In complete DiGeorge syndrome, patients have severely reduced T-cell function. Methods We treated five infants (age, one to four months) with complete DiGeorge syndrome by transplantation of cultured postnatal Thymus Tissue. Follow-up evaluations included immune phenotyping and proliferative studies of peripheral-blood mononuclear cells plus biopsy of the Thymus allograft. Thymic production of new T cells was assessed in peripheral blood by tests for T-cell–receptor recombination excision circles, which are formed from excised DNA during the rearrangement of T-cell–receptor genes. Results After the transplantation of Thymus Tissue, T-cell proliferative responses to mitogens developed in four of the five patients. Two of the patients survived with restoration of immune function; three patients died from infection or abnormalities unrelated to transplantation. Biopsies of grafted Thymus in the s...
Frances E. Ward - One of the best experts on this subject based on the ideXlab platform.
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Transplantation of Thymus Tissue in Complete DiGeorge Syndrome
The New England journal of medicine, 1999Co-Authors: M. Louise Markert, Andreas Boeck, Laura P. Hale, Amy Kloster, Tanya M. Mclaughlin, Milena N. Batchvarova, Daniel C. Douek, Richard A. Koup, Donna D. Kostyu, Frances E. WardAbstract:Background The DiGeorge syndrome is a congenital disorder that affects the heart, parathyroid glands, and Thymus. In complete DiGeorge syndrome, patients have severely reduced T-cell function. Methods We treated five infants (age, one to four months) with complete DiGeorge syndrome by transplantation of cultured postnatal Thymus Tissue. Follow-up evaluations included immune phenotyping and proliferative studies of peripheral-blood mononuclear cells plus biopsy of the Thymus allograft. Thymic production of new T cells was assessed in peripheral blood by tests for T-cell–receptor recombination excision circles, which are formed from excised DNA during the rearrangement of T-cell–receptor genes. Results After the transplantation of Thymus Tissue, T-cell proliferative responses to mitogens developed in four of the five patients. Two of the patients survived with restoration of immune function; three patients died from infection or abnormalities unrelated to transplantation. Biopsies of grafted Thymus in the s...