Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

Abstract

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.

Thymus Functionality Needs More Than a Few TECs

“…If genetic mutations are inherent to the hematopoietic cells, bone marrow transplants are an effective clinical treatment (159). However, individuals wherein the non-hematopoietic stromal/epithelial cells of the thymus are impacted, allogeneic thymus tissue transplants remain the only FDA approved therapy (Enzyvant, Inc.) (160)(161)(162). For such tissue transplants, the donor thymus is depleted of most hematopoietic cells, leaving a residual mixture of pericytes, endothelial cells, TECs, and some mature CD4 + T cells (160).…”

“…However, individuals wherein the non-hematopoietic stromal/epithelial cells of the thymus are impacted, allogeneic thymus tissue transplants remain the only FDA approved therapy (Enzyvant, Inc.) (160)(161)(162). For such tissue transplants, the donor thymus is depleted of most hematopoietic cells, leaving a residual mixture of pericytes, endothelial cells, TECs, and some mature CD4 + T cells (160). These transplant strategies work for those with a severe T cell lymphopenia.…”

“…These transplant strategies work for those with a severe T cell lymphopenia. Among the patients who will benefit from such transplants include those with 22q11.2 deletion syndrome (DiGeorge), autosomal recessive FOXN1 mutations, PAX1 mutations, CHARGE (Coloboma, heart defects, anal atresia, growth retardation, genital abnormalities, ear abnormalities) syndrome, or those who had diabetic embryopathies (6,80,160). However, the allogeneic transplant approach is not suitable for individuals who retain some thymus functionality, since they will have sufficient peripheral T cell numbers to cause transplant rejection.…”

Differentiation of Pluripotent Stem Cells Into Thymic Epithelial Cells and Generation of Thymic Organoids: Applications for Therapeutic Strategies Against APECED

“…Beyond APECED, other pathologies affecting the thymus are also caused by genetic defects. DiGeorges syndrome is caused by a microdeletion of the TBX1-containing chromosome region 22q11.2, nude SCID by mutations in the FOXN1 gene and Otofaciocervical Syndrome type 2 in the PAX1 gene ( 155 ). These conditions lead to partial or total athymia and life-threatening lymphopenia.…”

Inborn errors of immunity associated with defects of thymic development

“…Upon transplant, the recipient hematopoietic precursors migrate to the thymic implant, where they can differentiate into mature T‐cells and then repopulate the periphery. Thymus transplantation has been performed in well over 100 patients with an overall survival around 75% 59,136 . Infections, often acquired prior to transplantation, represent the most common cause of death in these patients, but autoimmunity and inflammatory complications are also relatively common 59,136 .…”