First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases

Abstract

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-Guérin 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.

Immune reconstitution following stem cell transplantation

“…66,67 Thymic tissue transplant has been used for the treatment of children with DiGeorge syndrome (congenital hypoplastic thymus). 68 A number of groups are employing tissue engineering techniques to create an artificial thymus, using various biomaterials, thymic epithelial precursor cells, and/or mesenchymal cells.…”

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

“…Notably although, the pioneering studies performed by Francis Albert Pierre Miller in the early 1960s had already pointed to the critical role of the thymus in T-cell generation [4]. More recently, the treatment of patients with thymic dysgenesis by allogeneic thymus tissue transplant has resulted in a rescue of their T-cell deficiency, highlighting the importance of the thymus in human T-cell differentiation [5,6]. This has also been extensively found to be the case in HIV-1 infection where immune reconstitution following highly active antiretroviral therapy has been shown to require an efficient thymopoiesis (reviewed in [7]).…”

Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

“…We propose CYR61 as an adjunctive treatment to thymus transplantation, which was performed successfully in patients with complete DiGeorge syndrome 34 or deficient for FoxN1 (ref. 35), and that restored T-cell production and function. Interestingly, CYR61 gene transfer has been used previously for therapeutic angiogenesis in models of lower-limb ischaemia 42 , ischaemic retinopathy 43 and experimental autoimmune myocarditis 44 .…”

“…As hematopoietic precursors are normal in nude, transplantation of WT-thymic lobes into nude mice re-establishes normal T-cell development 33 . Similarly, thymus transplantation in infants deficient for FoxN1 or with complete DiGeorge anomaly leads to T-cell reconstitution and to normal immune function 34,35 . Nude mice transplanted with CYR61-overexpressing lobes (CYR61-nude) or control lobes (control-nude) were monitored for 8 weeks.…”