Hematopoietic stem cell transplantation for CTLA4 deficiency

Slatter, Mary; Engelhardt, Karin R.; Burroughs, Lauri M.; Arkwright, Peter D.; Nademi, Zohreh; Skoda-Smith, Suzanne; Hagin, David; Kennedy, Alan; Barge, D; Flood, Terence; Abinun, Mario; Wynn, Robert; Gennery, Andrew R.; Cant, Andrew J.; Sansom, David M.; Hambleton, Sophie; Torgerson, Troy R.

doi:10.1016/j.jaci.2016.01.045

Cited by 85 publications

(71 citation statements)

References 13 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nine of these 12 were alive in 100 days to more than 5 years following procedure . Slatter et al presented the outcome of HSCT in eight patients with CTLA‐4 insufficiency. According to their report, most of patients recovered after HSCT; but, half of them developed severe graft‐versus‐host disease (GVHD) in spite of well‐matched donors and administration of alemtuzumab.…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

“…Slatter et al presented the outcome of HSCT in eight patients with CTLA‐4 insufficiency. According to their report, most of patients recovered after HSCT; but, half of them developed severe graft‐versus‐host disease (GVHD) in spite of well‐matched donors and administration of alemtuzumab. Either more enhanced immune suppression before HSCT or more aggressive GVHD prophylaxis might be required for planning of HSCT .…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

“…According to their report, most of patients recovered after HSCT; but, half of them developed severe graft‐versus‐host disease (GVHD) in spite of well‐matched donors and administration of alemtuzumab. Either more enhanced immune suppression before HSCT or more aggressive GVHD prophylaxis might be required for planning of HSCT . Therefore, it is generally accepted that HSCT should be considered in selected affected CTLA4 mutation carriers .…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

See 2 more Smart Citations

What did we learn from CTLA‐4 insufficiency on the human immune system?

Mitsuiki

Schwab

Grimbacher

2018

Immunological Reviews

123

View full text Add to dashboard Cite

Summary Cytotoxic‐T‐lymphocyte‐antigen‐4 (CTLA‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA‐4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA‐4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA‐4‐mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA‐4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty‐eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA‐4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA‐4‐insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA‐4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA‐4 insufficiency causes severe disease taught us that the amount of CTLA‐4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology‐causing activated T lymphocytes in CTLA‐4‐insufficient patients are antigen‐specific is an unsolved question. CTLA‐4, in addition, has a role in autoimmune diseases and cancer. Anti‐CTLA‐4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA‐4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA‐4 molecule and immune dysregulation disorders.

show abstract

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

See 1 more Smart Citation

What did we learn from CTLA‐4 insufficiency on the human immune system?

Mitsuiki

Schwab

Grimbacher

2018

Immunological Reviews

123

View full text Add to dashboard Cite

show abstract

“…At least 8 CHAI and 8 LATAIE patients have undergone HSCTs. [10][11][12][13]18,44,45 Eleven of the transplants were successful, although 1 died 2.5 years post-HSCT because of diabetic ketoacidosis. Three other transplants resulted in death shortly after transplant, and 2 outcomes have yet to be reported.…”

Section: Therapeutic Considerationsmentioning

confidence: 99%

CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency

Fritz

Su³

et al. 2016

Blood

126

115

View full text Add to dashboard Cite

CTLA-4 is a critical inhibitory “checkpoint” molecule of immune activation. Several recent reports have described patients with immune dysregulation and lymphoproliferative disease resulting from 2 different genetic diseases that directly or indirectly cause CTLA-4 deficiency. Numerous articles have also been published describing CTLA-4 blockade in cancer immunotherapy and its side effects, which are ultimately the consequence of treatment-induced CTLA-4 deficiency. Here, we review these 2 diseases and CTLA-4 blockade therapy, emphasizing the crucial role of CTLA-4 in immune checkpoint regulation.

show abstract

“…A recent study has reported on the outcome of hematopoietic stem cell transplantation (HSCT) in eight patients with CTLA4 haploinsufficiency associated with life-threatening, treatment-resistant manifestations of immune dysregulation 17 . One of the patients also had a history of Hodgkin lymphoma.…”

Section: Ctla4 Haploinsufficiencymentioning

confidence: 99%

Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders

Notarangelo

Fleisher

2017

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain of function (GOF) mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders moving beyond the more commonly seen loss of function mutations. The rapidly expanding genetic defects that have been identified in previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block over active or enhance under responsive cellular pathways. Selected primary immunodeficiences were chosen, whose genetic defects have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine forward.

show abstract

Hematopoietic stem cell transplantation for CTLA4 deficiency

Cited by 85 publications

References 13 publications

What did we learn from CTLA‐4 insufficiency on the human immune system?

What did we learn from CTLA‐4 insufficiency on the human immune system?

CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency

Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders

Contact Info

Product

Resources

About