Thymus transplantation for complete DiGeorge syndrome: European experience

E Graham Davies; Melissa Cheung; Kimberly Gilmour; Jesmeen Maimaris; Joe Curry; Anna Furmanski; Neil Sebire; Neil Halliday; Konstantinos Mengrelis; Stuart Adams; Jolanta Bernatoniene; Ronald Bremner; Michael Browning; Blythe Devlin; Hans Christian Erichsen; H Bobby Gaspar; Lizzie Hutchison; Winnie Ip; Marianne Ifversen; T Ronan Leahy; Elizabeth McCarthy; Despina Moshous; Kim Neuling; Malgorzata Pac; Alina Papadopol; Kathryn L Parsley; Luigi Poliani; Ida Ricciardelli; David M Sansom; Tiia Voor; Austen Worth; Tessa Crompton; M Louise Markert; Adrian J Thrasher

doi:10.1016/j.jaci.2017.03.020

Thymus transplantation for complete DiGeorge syndrome: European experience

E Graham Davies
, Melissa Cheung
, Kimberly Gilmour
, Jesmeen Maimaris
, Joe Curry
, Anna Furmanski
, Neil Sebire
, Neil Halliday
, Konstantinos Mengrelis
, Stuart Adams
, Jolanta Bernatoniene
, Ronald Bremner
, Michael Browning
, Blythe Devlin
, Hans Christian Erichsen
, H Bobby Gaspar
, Lizzie Hutchison
, Winnie Ip
, Marianne Ifversen
, T Ronan Leahy

Elizabeth McCarthy, Despina Moshous, Kim Neuling, Malgorzata Pac, Alina Papadopol, Kathryn L Parsley, Luigi Poliani, Ida Ricciardelli, David M Sansom, Tiia Voor, Austen Worth, Tessa Crompton, M Louise Markert, Adrian J Thrasher

Department of Paediatrics and Adolescent Medicine

137 Citations (Scopus)

Abstract

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 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 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.

Original language	English
Journal	The Journal of allergy and clinical immunology
Volume	140
Issue number	6
Pages (from-to)	1660-1670.e16
ISSN	0091-6749
DOIs	https://doi.org/10.1016/j.jaci.2017.03.020
Publication status	Published - Dec 2017

Keywords

Journal Article

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10.1016/j.jaci.2017.03.020

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Davies, E. G., Cheung, M., Gilmour, K., Maimaris, J., Curry, J., Furmanski, A., Sebire, N., Halliday, N., Mengrelis, K., Adams, S., Bernatoniene, J., Bremner, R., Browning, M., Devlin, B., Erichsen, H. C., Gaspar, H. B., Hutchison, L., Ip, W., Ifversen, M., ... Thrasher, A. J. (2017). Thymus transplantation for complete DiGeorge syndrome: European experience. The Journal of allergy and clinical immunology, 140(6), 1660-1670.e16. https://doi.org/10.1016/j.jaci.2017.03.020

Davies, EG, Cheung, M, Gilmour, K, Maimaris, J, Curry, J, Furmanski, A, Sebire, N, Halliday, N, Mengrelis, K, Adams, S, Bernatoniene, J, Bremner, R, Browning, M, Devlin, B, Erichsen, HC, Gaspar, HB, Hutchison, L, Ip, W, Ifversen, M, Leahy, TR, McCarthy, E, Moshous, D, Neuling, K, Pac, M, Papadopol, A, Parsley, KL, Poliani, L, Ricciardelli, I, Sansom, DM, Voor, T, Worth, A, Crompton, T, Markert, ML & Thrasher, AJ 2017, 'Thymus transplantation for complete DiGeorge syndrome: European experience', The Journal of allergy and clinical immunology, vol. 140, no. 6, pp. 1660-1670.e16. https://doi.org/10.1016/j.jaci.2017.03.020

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title = "Thymus transplantation for complete DiGeorge syndrome: European experience",

abstract = "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 {\texttimes} 106/L (range, 11-440 {\texttimes} 106/L) and 200 {\texttimes} 106/L (range, 5-310 {\texttimes} 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 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.",

keywords = "Journal Article",

author = "Davies, \{E Graham\} and Melissa Cheung and Kimberly Gilmour and Jesmeen Maimaris and Joe Curry and Anna Furmanski and Neil Sebire and Neil Halliday and Konstantinos Mengrelis and Stuart Adams and Jolanta Bernatoniene and Ronald Bremner and Michael Browning and Blythe Devlin and Erichsen, \{Hans Christian\} and Gaspar, \{H Bobby\} and Lizzie Hutchison and Winnie Ip and Marianne Ifversen and Leahy, \{T Ronan\} and Elizabeth McCarthy and Despina Moshous and Kim Neuling and Malgorzata Pac and Alina Papadopol and Parsley, \{Kathryn L\} and Luigi Poliani and Ida Ricciardelli and Sansom, \{David M\} and Tiia Voor and Austen Worth and Tessa Crompton and Markert, \{M Louise\} and Thrasher, \{Adrian J\}",

year = "2017",

month = dec,

doi = "10.1016/j.jaci.2017.03.020",

language = "English",

volume = "140",

pages = "1660--1670.e16",

journal = "The Journal of allergy and clinical immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "6",

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TY - JOUR

T1 - Thymus transplantation for complete DiGeorge syndrome

T2 - European experience

AU - Davies, E Graham

AU - Cheung, Melissa

AU - Gilmour, Kimberly

AU - Maimaris, Jesmeen

AU - Curry, Joe

AU - Furmanski, Anna

AU - Sebire, Neil

AU - Halliday, Neil

AU - Mengrelis, Konstantinos

AU - Adams, Stuart

AU - Bernatoniene, Jolanta

AU - Bremner, Ronald

AU - Browning, Michael

AU - Devlin, Blythe

AU - Erichsen, Hans Christian

AU - Gaspar, H Bobby

AU - Hutchison, Lizzie

AU - Ip, Winnie

AU - Ifversen, Marianne

AU - Leahy, T Ronan

AU - McCarthy, Elizabeth

AU - Moshous, Despina

AU - Neuling, Kim

AU - Pac, Malgorzata

AU - Papadopol, Alina

AU - Parsley, Kathryn L

AU - Poliani, Luigi

AU - Ricciardelli, Ida

AU - Sansom, David M

AU - Voor, Tiia

AU - Worth, Austen

AU - Crompton, Tessa

AU - Markert, M Louise

AU - Thrasher, Adrian J

PY - 2017/12

Y1 - 2017/12

N2 - 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 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 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.

AB - 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 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 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.

KW - Journal Article

U2 - 10.1016/j.jaci.2017.03.020

DO - 10.1016/j.jaci.2017.03.020

M3 - Journal article

C2 - 28400115

SN - 0091-6749

VL - 140

SP - 1660-1670.e16

JO - The Journal of allergy and clinical immunology

JF - The Journal of allergy and clinical immunology

IS - 6

ER -

Thymus transplantation for complete DiGeorge syndrome: European experience

Abstract

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