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Immunodeficiency in DiGeorge Syndrome and Options for Treating Cases with Complete Athymia.

Davies EG - Front Immunol (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Immunodeficiency, Institute of Child Health, University College London and Great Ormond Street Hospital , London , UK.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Low-power view of a biopsy of transplanted thymus stained with Hematoxylin and Eosin. Normal looking thymic tissue surrounded by striated muscle. There is good corticomedullary distinction.
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Figure 3: Low-power view of a biopsy of transplanted thymus stained with Hematoxylin and Eosin. Normal looking thymic tissue surrounded by striated muscle. There is good corticomedullary distinction.

Mentions: Replacement of thymic function using allografted tissue was first achieved using human fetal thymic tissue (104, 105). The use of post natal human thymus, necessarily removed at the time of cardiac surgery in infants undergoing median sternotomy, was pioneered by Markert at Duke University (106, 107) and has become established as the treatment of choice for cDGS. More recently this approach has also been used in London using an almost identical approach (manuscript in preparation). The thymus is cultured for 12–21 days prior to transplantation into the quadriceps muscle of the patient. During this period most thymocytes are washed out or undergo apoptosis whilst the thymic stroma is preserved. Patients with atypical cDGS are pre-treated with anti thymocyte globulin and continuing cyclosporine A (108) whilst typical cases receive no pre-conditioning. The results have been published (55, 109) and of 60 patients treated 43 survived (72%). This compares favorably with the outcome after HCT described above though strict comparison is not possible as the thymus transplant patients were a selected group. After successful transplantation, patients develop host derived naïve T cells with a normal T-cell receptor repertoire (Figure 2), normal mitogen responses and antigen specific immune responses restricted to the host major histocompatibility complex (MHC). There is normalization of the TCR repertoire in circulating regulatory T cells (110). Biopsies of transplanted thymus taken from 2 months onward show thymopoiesis (111) and normal thymus architecture (Figure 3). The levels of circulating T cells achieved do not usually match normal age matched controls and are more akin to the levels seen in children with pDGS. Tolerance to the donor’s MHC has been demonstrated (112) and this has been exploited to enable parathyroid transplantation from a parent in situations where there is coincidental partial MHC class 2 matching between the donor and the parent (113).


Immunodeficiency in DiGeorge Syndrome and Options for Treating Cases with Complete Athymia.

Davies EG - Front Immunol (2013)

Low-power view of a biopsy of transplanted thymus stained with Hematoxylin and Eosin. Normal looking thymic tissue surrounded by striated muscle. There is good corticomedullary distinction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814041&req=5

Figure 3: Low-power view of a biopsy of transplanted thymus stained with Hematoxylin and Eosin. Normal looking thymic tissue surrounded by striated muscle. There is good corticomedullary distinction.
Mentions: Replacement of thymic function using allografted tissue was first achieved using human fetal thymic tissue (104, 105). The use of post natal human thymus, necessarily removed at the time of cardiac surgery in infants undergoing median sternotomy, was pioneered by Markert at Duke University (106, 107) and has become established as the treatment of choice for cDGS. More recently this approach has also been used in London using an almost identical approach (manuscript in preparation). The thymus is cultured for 12–21 days prior to transplantation into the quadriceps muscle of the patient. During this period most thymocytes are washed out or undergo apoptosis whilst the thymic stroma is preserved. Patients with atypical cDGS are pre-treated with anti thymocyte globulin and continuing cyclosporine A (108) whilst typical cases receive no pre-conditioning. The results have been published (55, 109) and of 60 patients treated 43 survived (72%). This compares favorably with the outcome after HCT described above though strict comparison is not possible as the thymus transplant patients were a selected group. After successful transplantation, patients develop host derived naïve T cells with a normal T-cell receptor repertoire (Figure 2), normal mitogen responses and antigen specific immune responses restricted to the host major histocompatibility complex (MHC). There is normalization of the TCR repertoire in circulating regulatory T cells (110). Biopsies of transplanted thymus taken from 2 months onward show thymopoiesis (111) and normal thymus architecture (Figure 3). The levels of circulating T cells achieved do not usually match normal age matched controls and are more akin to the levels seen in children with pDGS. Tolerance to the donor’s MHC has been demonstrated (112) and this has been exploited to enable parathyroid transplantation from a parent in situations where there is coincidental partial MHC class 2 matching between the donor and the parent (113).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Immunodeficiency, Institute of Child Health, University College London and Great Ormond Street Hospital , London , UK.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus