Thymic transplantation for complete DiGeorge syndrome: Medical and surgical considerations

Rice, Henry E.; Skinner, Michael A.; Mahaffey, Samuel M.; Oldham, Keith T.; Ing, Richard J.; Hale, Laura P.; Markert, M. Louise

doi:10.1016/j.jpedsurg.2004.07.020

Cited by 51 publications

(56 citation statements)

References 38 publications

(31 reference statements)

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“…For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction. 14,17,18,20,[22][23][24][25][26][27][28][29][30][31]33,[35][36][37] In our collected cohort, B-and/or NK-cell numbers were reported in only 29 of 59 patients, and of these 29 patients, 1 had low B-cell numbers, 1 had high B-cell numbers, 1 had low NK-cells numbers and 3 had high NK-cell numbers. The reported B-and NK-cells numbers of other patients were normal.…”

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 77%

“…The reported B-and NK-cells numbers of other patients were normal. 14,23,[26][27][28][34][35][36] Immunoglobulin levels were reported in 33 of 59 patients and in 20 of 36 patients with a proven variant in CHD7. Hypogammaglobulinaemia was reported in 20 of 33 (61%) patients and measured along with T-cell lymphopenia in 14 of 18 (78%) patients.…”

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 97%

“…Of the 35 patients, 1 patient had T-cell lymphopenia and a transient B-cell lymphopenia, which normalized with ageing. [26][27][28] Thymic aplasia was reported in 27 of 59 patients and in 16 of 36 patients with a proven variant in CHD7. T-cell lymphopenia in our collected cohort was associated with thymic aplasia or hypoplasia in 21 of 22 (95%) patients.…”

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 99%

“…T-cell lymphopenia in our collected cohort was associated with thymic aplasia or hypoplasia in 21 of 22 (95%) patients. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] T-cell function by response on mitogens was available for 28 of 59 patients and of these 28 patients 24 (86%) had a low or absent response on mitogen. For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction.…”

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 99%

“…14,17,[22][23][24][25][26][27][28][29]35,36 Thirteen of 33 (39%) patients with known immunoglobulin levels had IgG deficiency and 2 of these patients had received immunoglobulin replacement therapy. 14,[16][17][18][22][23][24][25][26][27][28][29]38 Of these 13 patients with IgG deficiency, 6 had recurrent or chronic infections and 1 had absent specific antibody responses. 14,[16][17][18]22,24,25 Isolated immunoglobulin deficiencies were rarely reported in CHARGE syndrome.…”

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 99%

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CHARGE syndrome: a review of the immunological aspects

et al. 2015

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CHARGE syndrome is caused by a dominant variant in the CHD7 gene. Multiple organ systems can be affected because of haploinsufficiency of CHD7 during embryonic development. CHARGE syndrome shares many clinical features with the 22q11.2 deletion syndrome. Immunological abnormalities have been described, but are generally given little attention in studies on CHARGE syndrome. However, structured information on immunological abnormalities in CHARGE patients is necessary to develop optimal guidelines for diagnosis, treatment and follow-up in these patients. Here, we provide an overview of the current literature on immunological abnormalities in CHARGE syndrome. We also explore immunological abnormalities in comparable multiple congenital anomaly syndromes to identify common immunological phenotypes and genetic pathways that might regulate the immune system. Finally, we aim to identify gaps in our knowledge on the immunological aspects in CHARGE syndrome that need further study.

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Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 77%

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 97%

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 99%

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 99%

Section: Immunological Abnormalities Reported In Charge Syndromementioning

confidence: 99%

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CHARGE syndrome: a review of the immunological aspects

et al. 2015

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Improving thymus implantation for congenital athymia with interleukin‐7

Min,

Valente,

et al. 2023

Clin & Trans Imm

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ObjectivesThymus implantation is a recently FDA‐approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.MethodsUsing Foxn1nu athymic mice as recipients, we tested MHC‐matched and ‐mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL‐7 would promote the expansion of host naïve T cells educated by the implanted thymus.ResultsWe determined that thymus implants in Foxn1nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC‐mismatched donor thymus into Foxn1nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory‐like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC‐matched and ‐mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL‐7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL‐7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.ConclusionWe conclude that implanting cultured thymus into the muscle of Foxn1nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL‐7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.

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