Next-generation calcineurin inhibitors for ophthalmic indications

Calcineurin inhibitors (CNIs) are potent immunosuppressants that reversibly inhibit T-cell proliferation and prevent the release of pro-inflammatory cytokines by blocking the activity of calcineurin, a ubiquitous enzyme that is found in cell cytoplasm. CNIs can be highly effective in immune-mediated ophthalmic diseases such as uveitis, dry eye syndrome and inflammatory blepharitis, as well as for the prevention of rejection in corneal transplants. ISA-247/LX-211 is a novel CNI that is in Phase III clinical development for the treatment of various forms of non-infectious uveitis. ISA-247/LX-211 is a rationally designed analog of ciclosporin A that exhibits more predictable pharmacokinetic and pharmacodynamic properties and a 4-fold greater calcineurin inhibition than its parent compound, ciclosporin A. ISA-247/LX-211 has been observed to be effective, well-tolerated, and safe in early clinical trials, exhibiting a much wider therapeutic window compared with classic CNIs, such as ciclosporin A and tacrolimus. An alternative approach to widening the therapeutic window for the therapy of ophthalmic disorders lies in local delivery of CNIs through polymeric implants that release the drug over long periods of time. The silicone matrix episcleral implant LX-201 is in Phase III development at present for the prevention of rejection in high-risk cornea transplantation.     

Rejection sensitivity and multiple group memberships: The moderating role of an oxytocin receptor gene polymorphism

Rejection sensitivity is a cognitive-affective processing disposition that has been linked to interpersonal difficulties. In this regard, the neuropeptide hormone, oxytocin, is thought to underlie social cognitions and behaviors that promote social affiliation. A single nucleotide polymorphism (SNP) on the oxytocin receptor gene (OXTR), in which guanine (G) is substituted for adenine (A), has been associated with less support-seeking behaviors. In the current study, among 376 undergraduate students, it was shown that the relationship between rejection sensitivity and depressive symptoms was mediated by multiple group memberships. Furthermore, the relation between rejection sensitivity and group memberships was only evident among individuals possessing the A allele on the OXTR gene. These findings further support the psychosocial deficits characteristic of individuals possessing the OXTR polymorphism, which in turn is linked to poor mood.     

Some Consequences of being the Wrong Child: Effects of the Intergenerational Transmission of an Ideal‐Ego

In this paper the author considers a not uncommon group of patients seen in analytic work. These are people who present themselves for treatment because they feel that there is something ‘wrong with themselves’, and it is this belief about themselves that is their problem. They are usually people who have not achieved their potential in life; who may be dissatisfied in their relationships and/or with their level of success in their work. They often suffer from depression, symptoms of anxiety or psychosomatic complaints. In this way their belief in their sense of ‘wrongness’ is self‐confirming and to this extent they do have something wrong with them although the particular manifestations, of what is wrong, can vary considerably. However, it is what these people have in common, their fundamental belief in being ‘wrong’, which the author is going to address.     

Potential and limitations of regulatory T-cell therapy in solid organ transplantation

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.