Thymus Transplantation With Immunosuppression

DiGeorge Syndrome Clinical Trial

— 884  

Official title:

Thymus Transplantation With Immunosuppression, #884

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00579709
• Other study ID #: Pro00013734
• Secondary ID: R01AI047040R01AI
• Status: Completed
• Phase: Phase 1
• Start date: July 2002
• Est. completion date: December 2019

Study information

• Verified date: March 2022
• Source: Enzyvant Therapeutics GmBH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The research purpose is to determine if thymus transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly. The research includes studies to evaluate whether thymus transplantation results in complete DiGeorge anomaly subjects developing a normal immune system.

Description:

DiGeorge anomaly is a complex of cardiac defects, parathyroid deficiency, and thymus absence, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge anomaly with respect to all three defects. For complete DiGeorge anomaly subjects with severe T cell defect, the PI had shown that thymus transplantation is safe and efficacious without pretransplantation immunosuppression and with pretransplantation Thymoglobulin and cyclosporine.

Some DiGeorge patients have very poor T cell function and are at risk of death from infection or other immune problems; however, these patients have enough T cell function to reject grafts. This protocol was designed for these patients. Atypical phenotype and some typical phenotype DiGeorge subjects were included in this protocol.

Atypical complete DiGeorge anomaly patients have rash, lymphadenopathy, and oligoclonal T cell proliferations. The T cells have no markers of thymic function (they do not co-express CD45RA and CD62L; they do not contain T cell receptor rearrangement excision circles, TRECs).

Typical complete DiGeorge anomaly patients in this protocol are those whose PHA response >20 fold. Although these patients have very low T cell function, it may be enough to reject a transplant, so Thymoglobulin was used.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 2019
• Est. primary completion date: December 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Transplant Inclusion

• No age limit

• Thyroid studies must be done and if abnormal, must be on therapy

DiGeorge diagnosis - must have 1 symptom from the following list:

• Heart defect

• Hypocalcemia requiring replacement

• 22q11 hemizygosity

• 10p13 hemizygosity

• CHARGE association

• Abnormal ears plus mother with diabetes (type I, type II, or gestational)

Atypical Diagnosis:

• Must have, or have had, a rash. If rash present, biopsy of rash must show T cells in skin. If rash & adenopathy resolved, must still have oligoclonal T cells.

• Within 1 month of tx must have PHA response >20 fold above background or >5,000 cpm, whichever is higher, or response can be < this.

• Circulating CD3+ T cells >50/mm3 but CD45RA+CD62L+CD3+ T cells <50/mm or <5% of CD3 count, whichever is higher (must be done 2x)

• Immunoscope with >40% oligoclonal TCRBV families. A 2nd test per sponsor discretion if T cell numbers increase or activation status changes.

• If TREC done pre-tx must have TRECs <100 per 100,000 CD3+ cells.

Typical Diagnosis:

• Circulating CD3+ CD45RA+ CD62L+ T cells and <50/mm3 or <5% of total T cells

• PHA response >20 fold above background or >5,000 cpm, whichever is higher.

• 2 studies must show similar immunological findings qualify for this study.

• TRECs, if done, should be <100/100,000 CD3 cells

Transplant Exclusion:

• Heart surgery <4 weeks pre-tx date

• Heart surgery anticipated w/in 3 months of proposed tx

• Rejection by surgeon or anesthesiologist as surgical candidates

• Lack of sufficient muscle tissue to accept 0.2 grams/kg transplant

Related Conditions & MeSH terms

• Complete DiGeorge Anomaly
• Complete DiGeorge Syndrome
• Congenital Abnormalities
• Craniosynostoses
• DiGeorge Anomaly
• DiGeorge Syndrome
• Marfan Syndrome
• Syndrome

Intervention

Biological:
• Thymus Tissue for Transplantation
3 Thymoglobulin doses given prior to thymus tx. Atypical subjects given Cyclosporine (Csa) pre-tx. Desired Csa concentration 180-300ng/ml. If post-tx T cell count remained <4000/cumm Csa weaned over 8 weeks. If T cell >4,000/cumm, Csa held at 180-300ng/ml. Thymus tissue, donor, & mother of donor were screened for transplant safety. In operating room, thymic slices were transplanted into quadriceps muscle in 1 or both legs. Subjects had routine blood research immune evaluations. 2-3 months post-tx, open biopsy of allograft. Immune blood studies continued on surviving subjects until January 2010. Biological Mother: Mother provided blood sample used for DNA extraction, to identify/look for maternal T cell presence in recipient pre-tx, and/or for immune testing post-tx.

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
Enzyvant Therapeutics GmBH	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (17)

Albuquerque AS, Marques JG, Silva SL, Ligeiro D, Devlin BH, Dutrieux J, Cheynier R, Pignata C, Victorino RM, Markert ML, Sousa AE. Human FOXN1-deficiency is associated with aß double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon — View Citation

Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. Epub 2007 Dec 26. — View Citation

Chinn IK, Milner JD, Scheinberg P, Douek DC, Markert ML. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly. Clin Exp Immunol. 2013 Jul;173(1):140-9. doi: 10.1111/cei.12088. — View Citation

Chinn IK, Olson JA, Skinner MA, McCarthy EA, Gupton SE, Chen DF, Bonilla FA, Roberts RL, Kanariou MG, Devlin BH, Markert ML. Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. J Allergy Clin Immunol. 2010 Oct;126(4):814-820.e8. doi: 10.1016/j.jaci.2010.07.016. Epub 2010 Sep 15. — View Citation

Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. Epub 2007 Nov 26. Review. — View Citation

Markert ML and Devlin BH. Thymic reconstitution (in Rich RR, Shearer WT, Fleischer T, Schroeder HW, Weyand CM, Frew A, eds., Clinical Immunology 3rd edn., Elsevier, Edinburgh) p 1253-1262, 2008.

Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA. Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood. 2004 Oct 15;104(8):2574- — View Citation

Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sempowski GD, Rhein ME, Szabolcs P, Hale LP, Buckley RH, Coyne KE, Rice HE, Mahaffey SM, Skinner MA. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells — View Citation

Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outco — View Citation

Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. doi: 10.1111/j.1600-6143.2008.02301.x. Epub 2008 Jun 28. — View Citation

Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70. doi: 10.1007/s12026-008-8082-5. — View Citation

Markert ML, Devlin BH, McCarthy EA, Chinn IK, Hale LP. Thymus Transplantation in Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. Eds Lavinin C, Moran CA, Morandi U, Schoenhuber R. Springer-Verlag Italia, Milan, 2008, pp 255-267.

Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. doi: 10.1016/j.clim.2010.02.007. Epub 2010 Mar 16. Review. — View Citation

Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64. — View Citation

Markert ML, Marques JG, Neven B, Devlin BH, McCarthy EA, Chinn IK, Albuquerque AS, Silva SL, Pignata C, de Saint Basile G, Victorino RM, Picard C, Debre M, Mahlaoui N, Fischer A, Sousa AE. First use of thymus transplantation therapy for FOXN1 deficiency ( — View Citation

Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. Epub 2003 Apr 17. — View Citation

Selim MA, Markert ML, Burchette JL, Herman CM, Turner JW. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008 Apr;35(4):380-5. doi: 10.1111/j.1600-0560.2007.00816.x. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety & tolerability of Thymoglobulin and cyclosporine followed by thymus transplantation: Survival at 1 year post-transplantation.		1 year post-transplantation
Secondary	Use of additional post transplant immunosuppression after that listed in the protocol.	Use of additional post transplant immunosuppression after that listed in the protocol.	The post thymus transplantation period
Secondary	Allograft biopsy used to evaluate graft rejection	Evidence of thymus allograft rejection by immunohistochemistry of biopsy	2 to 4 months post-transplant
Secondary	CD3 count	CD3 count in cells/mm3	10 - 14 months post-transplantation
Secondary	Thymopoiesis	Evidence of thymopoiesis in thymus allograft by immunohistochemistry of a biopsy	2-4 months after thymus transplantation
Secondary	CD4 count	CD4 count in cells/mm3	10-14 months after thymus transplantation
Secondary	CD8 count	CD8 count in cells/mm3	10-14 months after thymus transplantation
Secondary	naive CD4 count	naive CD4 count in cells/mm3	10-14 months after thymus transplantation
Secondary	naive CD8 count	naive CD8 count in cells/mm3	10-14 months after thymus transplantation