EditorialDead on Arrival: Understanding the Failure of CTLA4-Immunoglobulin Therapy in Inflammatory Bowel Disease
Section snippets
What Is Costimulation?
T cells are educated in the thymus to avoid responses to self-antigens through complex pathways of positive and negative selection. T cells that then enter the peripheral circulation are considered to be naive, antigen-inexperienced cells that migrate extensively through secondary lymphoid structures such as the spleen and lymph nodes. Activation of a naive T cell in a secondary lymphoid organ requires 3 signals (Figure 1A). Signal 1 is provided by a MHC class II (HLA-DR, -DP, or -DQ) or MHC
CTLA4-Ig and Blockade of Costimulation as an Immunotherapeutic Mechanism
Costimulatory blockade has emerged as an appealing methodologic approach in the treatment of a variety of inflammatory disorders considered to be T-cell driven. Most experience has been gathered with blockade of the CD28–CD80 and CD86 system via a genetically engineered fusion protein that chimerizes CTLA4 to the Fc portion of IgG (CTLA4-Ig; abatacept). Mechanistically, because of its much greater affinity for CD80 and CD86, CTLA4-Ig is thought to outcompete CD28 binding (Figure 1C). CTLA4-Ig
What Can Be Learned From the Abatacept Experience in IBD?
At a mechanistic level, there may be many potential, non-mutually exclusive explanations for this clinical result. Perhaps the most cogent reason is the relative lack of dependence on costimulation that TEM cells, the predominant type of T cell in the gut, exhibit. Costimulation is generally much more critical during the activation of naive T cells and less so for memory and TEM cells.15 This may also underlie the preferential efficacy of CTLA4-Ig in the therapy of early compared with late type
The Path Forward?
Do these studies represent the death-knell for blocking costimulation as a means to affect IBD? The answer is likely no. Next-generation forms of abatacept, such as CTLA4-Ig with a higher affinity for CD80 and CD86 such as belatacept (L104E and A29Y mutations in CTLA4), result in significantly improved clinical efficacy, such as in transplant medicine.21 Another aspect worth considering is the confounding variable introduced by azathioprine or 6-mercaptopurine that target CD28 signaling and
Acknowledgments
The authors thank Dr Josh Korzenik for helpful discussions and Dr Lukas Niederreiter for help with the illustration.
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Funding RSB was supported by NIH DK051362, DK044319, DK053056, DK088199, Harvard Digestive Diseases Center (NIH DK034854); AK by the European Research Council Grant agreement n° 260961 and the National Institute for Health Research Cambridge Biomedical Research Centre. LM was supported by NIH AI044236, AI084952, DK072201 and DK086605.
Conflicts of interest The authors disclose no conflicts.