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Graham E Davies - One of the best experts on this subject based on the ideXlab platform.
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replacing defective Thymus function
Current Opinion in Allergy and Clinical Immunology, 2020Co-Authors: Alexandra Y Kreins, Graham E DaviesAbstract:Purpose of review Transplantation of cultured postnatal allogeneic Thymus has been successful for treating athymia, mostly associated with complete DiGeorge syndrome, for more than 20 years. Advances in molecular genetics provide opportunities for widening the range of athymic conditions that can be treated while advances in cell culture and organ/tissue regeneration may offer the prospect of alternative preparations of thymic tissue. There are potential broader applications of this treatment outside congenital athymia. Recent findings At the same time as further characterization of the cultured Thymus product in terms of thymic epithelial cells and lymphoid composition, preclinical studies have looked at de-novo generation of thymic epithelial cells from stem cells and explored scaffolds for delivering these as three-dimensional structures. In the era of newborn screening for T-cell lymphopaenia, a broadening range of defects leading to athymia is being recognized and new assays should allow differentiation of these from haematopoietic cell defects, pending their genetic/molecular characterization. Evidence suggests that the tolerogenic effect of transplanted Thymus could be exploited to improve outcomes after solid organ Transplantation. Summary Thymus Transplantation, the accepted standard treatment for complete DiGeorge syndrome is also appropriate for other genetic defects leading to athymia. Improved strategies for generating Thymus may lead to better outcomes and broader application of this treatment.
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Thymus Transplantation for complete digeorge syndrome european experience
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Graham E Davies, Melissa Cheung, Kimberly Gilmour, Jesmeen Maimaris, Joe Curry, Anna L Furmanski, N J Sebire, Neil HallidayAbstract:Background Thymus Transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods Twelve patients with cDGS underwent Transplantation with allogeneic cultured Thymus. Objective We sought to confirm and extend the results previously obtained in a single center. Results Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after Transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after Transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 10 6 /L (range, 11-440 × 10 6 /L) and 200 × 10 6 /L (range, 5-310 × 10 6 /L) at 12 and 24 months after Transplantation and T-cell receptor excision circles were 2,238/10 6 T cells (range, 320-8,807/10 6 T cells) and 4,184/10 6 T cells (range, 1,582-24,596/10 6 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). Conclusions This study confirms the previous reports that Thymus Transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.
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T-Cell Reconstitution after Thymus XenoTransplantation Induces
2016Co-Authors: Hair Depigmentation, Graham E Davies, Anna L Furmanski, Jose Ignacio Saldana, Michael P Blundell, Adrian J Thrasher, Ryan F. L. O’shaughnessy, Neil J. Sebire, Tessa CromptonAbstract:Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, Thymus Transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of Thymus Transplantation by subcutaneously implanting human Thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG / recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4þ T cells alone. Immunofluorescent analysis suggested that Trp2þ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens
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immunodeficiency in digeorge syndrome and options for treating cases with complete athymia
Frontiers in Immunology, 2013Co-Authors: Graham E DaviesAbstract:The commonest association of thymic stromal deficiency resulting in T-cell immunodeficiency is the DiGeorge syndrome (DGS). This results from abnormal development of the third and fourth pharyngeal arches and is most commonly associated with a microdeletion at chromosome 22q11 though other genetic and non-genetic causes have been described. The immunological competence of affected individuals is highly variable, ranging from normal to a severe combined immunodeficiency when there is complete athymia. In the most severe group, correction of the immunodeficiency can be achieved using Thymus allografts which can support thymopoiesis even in the absence of donor-recipient matching at the major histocompatibility loci. This review focuses on the causes of DGS, the immunological features of the disorder, and the approaches to correction of the immunodeficiency including the use of Thymus Transplantation.
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t cell reconstitution after Thymus xenoTransplantation induces hair depigmentation and loss
Journal of Investigative Dermatology, 2013Co-Authors: Anna L Furmanski, Graham E Davies, N J Sebire, Ryan F L Oshaughnessy, Jose Ignacio Saldana, Michael P Blundell, Adrian J Thrasher, Tessa CromptonAbstract:Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, Thymus Transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of Thymus Transplantation by subcutaneously implanting human Thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG(-/-) recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4+ T cells alone. Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens.
Louise M Markert - One of the best experts on this subject based on the ideXlab platform.
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Transplantation Postnatal Thymus Transplantation with immunosuppression as treatment for DiGeorge syndrome
2016Co-Authors: Louise M Markert, Laura P. Hale, Marcella Sarzotti, Daniel A Ozaki, Gregory D Sempowski, Marilyn J Alexieff, Blythe H. Devlin, Debra A. Sedlak, Henry E RiceAbstract:Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppres-sion followed by postnatal Thymus trans-plantation would lead to T-cell function in 6 infant patients who had host T cells at the time of Transplantation. All infants had fewer than 50 recent thymic emi-grants (CD3CD45RACD62L) per cu-bic millimeter (mm3) and all had some proliferative response to the mitogen phytohemagglutinin. Four infants had rash, lymphadenopathy, and oligoclonal populations of T cells in the periphery. Five of 6 patients are alive at the fol-low-up interval of 15 months to 30 months. The 5 surviving patients devel-oped a mean of 983 host CD3 T cells/ mm3 (range, 536/mm3-1574/mm3), a mean of 437 recent thymic emigrants/mm3 (range, 196/mm3-785/mm3), and normal proliferative responses to phytohema-glutinin (follow-up from day 376 to day 873). The TCR repertoire became poly-clonal in patients who presented with oligoclonal T cells. All patients had thy-mopoiesis on allograft biopsy. Postnatal Thymus Transplantation after treatment with Thymoglobulin shows promise as therapy for infants with complete DiGeorge syn-drome who have significant proliferative re-sponses to mitogens or who develop rash, lymphadenopathy, and oligoclonal T cells
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T: The dynamics of T-cell receptor repertoire diversity following Thymus Transplantation in Digeorge anomaly
2016Co-Authors: Stanca M. Ciupe, Louise M Markert, Blythe H. Devlin, Thomas B KeplerAbstract:T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the Thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after Thymus Transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRb V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoir
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induction of tolerance to parental parathyroid grafts using allogeneic Thymus tissue in patients with digeorge anomaly
The Journal of Allergy and Clinical Immunology, 2011Co-Authors: Ivan K. Chinn, Louise M MarkertAbstract:DiGeorge anomaly can affect both thymic and parathyroid function. Although athymia is corrected by allogeneic Thymus Transplantation, treatment options for hypoparathyroidism have been unsatisfactory. Parathyroid Transplantation offers the potential for definitive cure but remains challenging because of graft rejection. Some allogeneic parathyroid grafts have functioned in adult recipients in the context of immunosuppression for renal Transplantation. Other efforts have attempted to reduce the allogenicity of the parathyroid grafts through manipulation of the parathyroid tissues before Transplantation (by using encapsulation or special culture techniques). Recently, we demonstrated the efficacy of parental parathyroid Transplantation when combined with allogeneic Thymus Transplantation in an infant with complete DiGeorge anomaly. The recipient developed tolerance toward the parathyroid donor. The parathyroid graft has functioned for 5 years after Transplantation without the need for continued immunosuppression or calcium supplementation. We observed that matching of the allogeneic Thymus graft to the parathyroid donor HLA class II alleles that are unshared with the recipient appears to be associated with the induction of tolerance toward the parathyroid graft. Further work is needed to determine the optimal means for using combined allogeneic Thymus and parental parathyroid Transplantation to correct hypoparathyroidism in patients with both complete and partial DiGeorge anomaly.
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first use of Thymus Transplantation therapy for foxn1 deficiency nude scid a report of 2 cases
Blood, 2011Co-Authors: Louise M Markert, Elizabeth A. Mccarthy, Blythe H. Devlin, Ivan K. Chinn, Jose Goncalo Marques, Benedicte Neven, Adriana S Albuquerque, Susana L Silva, Claudio PignataAbstract:FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal Thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guerin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given Thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after Transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The preTransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after Transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, Thymus Transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
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review of 54 patients with complete digeorge anomaly enrolled in protocols for Thymus Transplantation outcome of 44 consecutive transplants
Blood, 2007Co-Authors: Louise M Markert, Laura P. Hale, Marcella Sarzotti, Marilyn J Alexieff, Elizabeth A. Mccarthy, Stephanie E. Gupton, Blythe H. Devlin, Ivan K. Chinn, Thomas B Kepler, Michael A. SkinnerAbstract:The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of Thymus Transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, Thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive Thymus Transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-Transplantation follow-up as long as 13 years. All deaths occurred within 12 months of Transplantation. All 25 subjects who were tested 1 year after Transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after Transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus Transplantation was well tolerated and resulted in stable immunoreconstitution in these infants.
Ivan K. Chinn - One of the best experts on this subject based on the ideXlab platform.
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induction of tolerance to parental parathyroid grafts using allogeneic Thymus tissue in patients with digeorge anomaly
The Journal of Allergy and Clinical Immunology, 2011Co-Authors: Ivan K. Chinn, Louise M MarkertAbstract:DiGeorge anomaly can affect both thymic and parathyroid function. Although athymia is corrected by allogeneic Thymus Transplantation, treatment options for hypoparathyroidism have been unsatisfactory. Parathyroid Transplantation offers the potential for definitive cure but remains challenging because of graft rejection. Some allogeneic parathyroid grafts have functioned in adult recipients in the context of immunosuppression for renal Transplantation. Other efforts have attempted to reduce the allogenicity of the parathyroid grafts through manipulation of the parathyroid tissues before Transplantation (by using encapsulation or special culture techniques). Recently, we demonstrated the efficacy of parental parathyroid Transplantation when combined with allogeneic Thymus Transplantation in an infant with complete DiGeorge anomaly. The recipient developed tolerance toward the parathyroid donor. The parathyroid graft has functioned for 5 years after Transplantation without the need for continued immunosuppression or calcium supplementation. We observed that matching of the allogeneic Thymus graft to the parathyroid donor HLA class II alleles that are unshared with the recipient appears to be associated with the induction of tolerance toward the parathyroid graft. Further work is needed to determine the optimal means for using combined allogeneic Thymus and parental parathyroid Transplantation to correct hypoparathyroidism in patients with both complete and partial DiGeorge anomaly.
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first use of Thymus Transplantation therapy for foxn1 deficiency nude scid a report of 2 cases
Blood, 2011Co-Authors: Louise M Markert, Elizabeth A. Mccarthy, Blythe H. Devlin, Ivan K. Chinn, Jose Goncalo Marques, Benedicte Neven, Adriana S Albuquerque, Susana L Silva, Claudio PignataAbstract:FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal Thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guerin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given Thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after Transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The preTransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after Transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, Thymus Transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
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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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review of 54 patients with complete digeorge anomaly enrolled in protocols for Thymus Transplantation outcome of 44 consecutive transplants
Blood, 2007Co-Authors: Louise M Markert, Laura P. Hale, Marcella Sarzotti, Marilyn J Alexieff, Elizabeth A. Mccarthy, Stephanie E. Gupton, Blythe H. Devlin, Ivan K. Chinn, Thomas B Kepler, Michael A. SkinnerAbstract:The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of Thymus Transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, Thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive Thymus Transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-Transplantation follow-up as long as 13 years. All deaths occurred within 12 months of Transplantation. All 25 subjects who were tested 1 year after Transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after Transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus Transplantation was well tolerated and resulted in stable immunoreconstitution in these infants.
Blythe H. Devlin - One of the best experts on this subject based on the ideXlab platform.
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Transplantation Postnatal Thymus Transplantation with immunosuppression as treatment for DiGeorge syndrome
2016Co-Authors: Louise M Markert, Laura P. Hale, Marcella Sarzotti, Daniel A Ozaki, Gregory D Sempowski, Marilyn J Alexieff, Blythe H. Devlin, Debra A. Sedlak, Henry E RiceAbstract:Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppres-sion followed by postnatal Thymus trans-plantation would lead to T-cell function in 6 infant patients who had host T cells at the time of Transplantation. All infants had fewer than 50 recent thymic emi-grants (CD3CD45RACD62L) per cu-bic millimeter (mm3) and all had some proliferative response to the mitogen phytohemagglutinin. Four infants had rash, lymphadenopathy, and oligoclonal populations of T cells in the periphery. Five of 6 patients are alive at the fol-low-up interval of 15 months to 30 months. The 5 surviving patients devel-oped a mean of 983 host CD3 T cells/ mm3 (range, 536/mm3-1574/mm3), a mean of 437 recent thymic emigrants/mm3 (range, 196/mm3-785/mm3), and normal proliferative responses to phytohema-glutinin (follow-up from day 376 to day 873). The TCR repertoire became poly-clonal in patients who presented with oligoclonal T cells. All patients had thy-mopoiesis on allograft biopsy. Postnatal Thymus Transplantation after treatment with Thymoglobulin shows promise as therapy for infants with complete DiGeorge syn-drome who have significant proliferative re-sponses to mitogens or who develop rash, lymphadenopathy, and oligoclonal T cells
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T: The dynamics of T-cell receptor repertoire diversity following Thymus Transplantation in Digeorge anomaly
2016Co-Authors: Stanca M. Ciupe, Louise M Markert, Blythe H. Devlin, Thomas B KeplerAbstract:T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the Thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after Thymus Transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRb V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoir
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first use of Thymus Transplantation therapy for foxn1 deficiency nude scid a report of 2 cases
Blood, 2011Co-Authors: Louise M Markert, Elizabeth A. Mccarthy, Blythe H. Devlin, Ivan K. Chinn, Jose Goncalo Marques, Benedicte Neven, Adriana S Albuquerque, Susana L Silva, Claudio PignataAbstract:FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal Thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guerin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given Thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after Transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The preTransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after Transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, Thymus Transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
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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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review of 54 patients with complete digeorge anomaly enrolled in protocols for Thymus Transplantation outcome of 44 consecutive transplants
Blood, 2007Co-Authors: Louise M Markert, Laura P. Hale, Marcella Sarzotti, Marilyn J Alexieff, Elizabeth A. Mccarthy, Stephanie E. Gupton, Blythe H. Devlin, Ivan K. Chinn, Thomas B Kepler, Michael A. SkinnerAbstract:The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of Thymus Transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, Thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive Thymus Transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-Transplantation follow-up as long as 13 years. All deaths occurred within 12 months of Transplantation. All 25 subjects who were tested 1 year after Transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after Transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus Transplantation was well tolerated and resulted in stable immunoreconstitution in these infants.
Anna L Furmanski - One of the best experts on this subject based on the ideXlab platform.
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Thymus Transplantation for complete digeorge syndrome european experience
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Graham E Davies, Melissa Cheung, Kimberly Gilmour, Jesmeen Maimaris, Joe Curry, Anna L Furmanski, N J Sebire, Neil HallidayAbstract:Background Thymus Transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods Twelve patients with cDGS underwent Transplantation with allogeneic cultured Thymus. Objective We sought to confirm and extend the results previously obtained in a single center. Results Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after Transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after Transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 10 6 /L (range, 11-440 × 10 6 /L) and 200 × 10 6 /L (range, 5-310 × 10 6 /L) at 12 and 24 months after Transplantation and T-cell receptor excision circles were 2,238/10 6 T cells (range, 320-8,807/10 6 T cells) and 4,184/10 6 T cells (range, 1,582-24,596/10 6 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). Conclusions This study confirms the previous reports that Thymus Transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.
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T-Cell Reconstitution after Thymus XenoTransplantation Induces
2016Co-Authors: Hair Depigmentation, Graham E Davies, Anna L Furmanski, Jose Ignacio Saldana, Michael P Blundell, Adrian J Thrasher, Ryan F. L. O’shaughnessy, Neil J. Sebire, Tessa CromptonAbstract:Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, Thymus Transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of Thymus Transplantation by subcutaneously implanting human Thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG / recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4þ T cells alone. Immunofluorescent analysis suggested that Trp2þ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens
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t cell reconstitution after Thymus xenoTransplantation induces hair depigmentation and loss
Journal of Investigative Dermatology, 2013Co-Authors: Anna L Furmanski, Graham E Davies, N J Sebire, Ryan F L Oshaughnessy, Jose Ignacio Saldana, Michael P Blundell, Adrian J Thrasher, Tessa CromptonAbstract:Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, Thymus Transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of Thymus Transplantation by subcutaneously implanting human Thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG(-/-) recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4+ T cells alone. Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens.