Case report: Challenges in immune reconstitution following hematopoietic stem cell transplantation for CTLA-4 insufficiency-like primary immune regulatory disorders

Abstract

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is a T-cell hyperactivation disorder that can manifest with both immunodeficiency and immune dysregulation. Approximately one-third of patients may present mild symptoms and remain stable under supportive care. The remaining patients may develop severe multiorgan autoimmunity requiring lifelong immunosuppressive treatment. Hematopoietic stem cell transplantation (HSCT) is potentially curable for patients with treatment-resistant immune dysregulation. Nevertheless, little experience is reported regarding the management of complications post-HSCT. We present case 1 (CTLA-4 haploinsufficiency) and case 2 (CTLA-4 insufficiency-like phenotype) manifesting with severe autoimmunity including cytopenia and involvement of the central nervous system (CNS), lung, and gut and variable impairment of humoral responses. Both patients underwent HSCT for which the main complications were persistent mixed chimerism, infections, and immune-mediated complications [graft-versus-host disease (GVHD) and nodular lung disease]. Detailed management and outcomes of therapeutic interventions post-HSCT are discussed. Concretely, post-HSCT abatacept and human leukocyte antigen (HLA)-matched sibling donor lymphocyte infusions may be used to increase T-cell donor chimerism with the aim of correcting the immune phenotype of CTLA-4 haploinsufficiency.

Changes in Treg and Breg cells in a healthy pediatric population

“…CTLA-4 is a co-inhibitory surface molecule that is constitutively expressed in Treg and its expression assay is of great interest for the diagnosis and clinical management of both PIRDs (75-78) and autoimmune diseases (rheumatic diseases) (79). For instance, we and others analyzed the CTLA-4 expression in Treg to evaluate patients with immune dysregulation when no genetics were identified (75)(76)(77). In addition, given the suppressive capacity of CTLA-4, the use of CTLA-4-Ig (fusion protein: IgG1 Fc+CTLA-4) is an effective approach in treating CTLA-4 haploinsufficiency.…”

Treg in inborn errors of immunity: gaps, knowns and future perspectives

“…This approach becomes essential in patients that cannot be managed by immunosuppressive treatments ( 125 ). In this context, patients show an increased risk of alloreactivity to HSCT indicating a need for further research into the use of targeted treatment as a bridge for HSCT ( 134 ). Moreover, while this approach has demonstrated efficacy in resolving clinical symptoms for a subset of patients, the long-term survival rates remain relatively low compared to conventional IEIs.…”

“…Moreover, while this approach has demonstrated efficacy in resolving clinical symptoms for a subset of patients, the long-term survival rates remain relatively low compared to conventional IEIs. For PIRD, the survival rate at the 5-year mark is approximately 67% ( 135 ) whilst conventional IEIs exhibit a 90% ( 134 ). Regarding HSCT in PIRD, even when the donor is a close relative, genetic screening becomes necessary due to the disease’s delayed and variable clinical onset or incomplete penetrance, which could also potentially impact other family members ( 134 ).…”

“…For PIRD, the survival rate at the 5-year mark is approximately 67% ( 135 ) whilst conventional IEIs exhibit a 90% ( 134 ). Regarding HSCT in PIRD, even when the donor is a close relative, genetic screening becomes necessary due to the disease’s delayed and variable clinical onset or incomplete penetrance, which could also potentially impact other family members ( 134 ). Therefore, comprehensive research is imperative to render HSCT in PIRD a safer, more efficient and viable therapeutic approach.…”

Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches

“…As improving organ function is vital for achieving better HSCT outcomes, patients with CTLA-4 haploinsufficiency or LRBA deficiency might benefit from the use of Abatacept as a bridge to HSCT, rather than as continuative chronic treatment. In addition, the optimal minimal chimerism sufficient for achieving clinical and immunological control of the disease is still unclear [ 55 ▪ ]. Finally, the results of a CRISPR-Cas9 gene editing for CTLA-4 haploinsufficiency have been recently published: the adopted approach led to CTLA-4 protein restoration and effective CD80/CD86 transendocytosis both in in vitro patients’ T cells and in vivo ctla-4 −/− mouse model, opening the possibility for a safer yet equally effective curative option than HSCT [ 56 ▪▪ ].…”