Clinical Trial of CTLA4-Ig in Multiple Sclerosis
The immune system self-regulates itself through many mechanisms, for example, thymic deletion of autoreactive cells, the need for co-stimulation for activation of T cells, and also through T regulatory (Treg) cells that recognize proteins that belong to the body and stop other T cells from attacking these proteins. Another way in which activated T cells control themselves is by increasing expression of a molecule called CTLA-4.
This molecule works through several means. One is outcompeting CD28 for access to CD80 and CD86 on the antigen presenting cell, the other is by sending a suppressive signal to the antigen presenting cell.
To activate a T cell, generally speaking, one requires 2 main signals, the T cell receptor (TCR) has to recognize a major histocompatibility complex (MHC) molecule that has a peptide inside of it. If the TCR appropriately “fits” into the MHC-peptide complex, then the TCR sends a signal into the T cell. However this first signal is not enough to activate the T cell. The T cell requires another signal from the antigen presenting cell. This second signal, also called costimulatory signal, is usually in the form of CD80 and/or CD86 from the antigen presenting cell, which both bind to CD28 on the T cell. The activation of CD28 and the TCR on the T cell results in T cell activation. When only the TCR is activated without CD28, then the T cell either goes into a state of prolonged unresponsiveness (called anergy), or in some situations actually can start expressing immune suppressive properties. CTLA4 is turned on by the T cell after the T cell is activated. CTLA4 binds with much higher affinity to CD80 and CD86 than does CD28. Therefore, after T cell activation, the T cell can “turn itself off” by expressing CTLA4.
Studies have demonstrated that activated T cells expressing CTLA4 can bind to dendritic cells (most potent antigen presenting cells), and that the CTLA4 on the activated T cell sents a negative signal to the dendritic cell, inducing the dendritic cell to secrete immune suppressive proteins and upregulate expression of the enzyme indolamine 2,3 deoxygenase (IDO) which in turn suppresses other T cells.
Interestingly CTLA4 is expressed not only by activated T cells but also by Treg cells.
Given the ability of CTLA4 to suppress immune responses via at least 2 mechanisms (more are known), scientists have tried to use CTLA4 therapeutically. To make a soluble form of CTLA4 that can be administered, a pharmaceutical form has been developed by fusing the protein CTLA4 with the immunoglobulin domain of IgG, to make a chimeric molecule called CTLA4-Ig. Currently CTLA4-Ig is sold by Bristol Myers Squibb under the name Abatacept (Orencia) for the treatment of rheumatoid arthritis that is nonresponsive to TNF-alpha inhibitors such as Remicade.
Given the immune modulatory properties of CTLA4-Ig, one question is whether it may inhibit suppress autoimmune responses in patients with multiple sclerosis. A recent study (Viglietta et al. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology 2008 Sep 16;71(12):917-24) assessed this in a small clinical trial.
The investigators performed a Phase I trial, meaning that the primary endpoint was toxicity and ability to identify therapeutic dose for subsequent Phase II investigations. A total of 20 patients with relapse remitting multiple sclerosis were treated with intravenous infusions of CTLA4-Ig and monitored for 3 months.
CTLA4-Ig administration correlated with suppression of interferon gamma production and proliferation in response to myelin basic protein ex vivo. The treatment elicited no serious treatment associated adverse events, although some mild adverse events were reported.
This study demonstrated feasibility of CTLA4-Ig administration in relapse remitting multiple sclerosis, and provides support for further Phase II trials.
Unfortunately CTLA4-Ig is still a non-specific immune suppressant in that it globally inhibits activation of T cells and theoretically could predispose to infections. One important question is whether the CTLA4-Ig administration may help to “reprogram” the immune system so as to promote eventual tolerance to the myelin antigens while leaving immunity to extracorporal antigens intact.
A possible approach would be to use CTLA4-Ig in combination with antigen-specific approaches such as vaccination with autoreactive T cells. Additionally, it will be important to assess the effects of CTLA4-Ig on Treg cells. For example, we know that interferon beta, which induces therapeutic effects in multiple sclerosis stimulates Treg activity. We also know from animal studies (Salomon et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. 2000 Apr;12(4):431-40) that administration of CTLA4-Ig can actually block Treg generation, so if interferon beta works through Treg generation, the combination may not work.