The preceding sections establish that CD40 signals make important contributions to initiation and progression of many autoimmune diseases (). Strategies for alleviating these diseases by inhibiting CD40 signaling have been ongoing for over a decade, recently reviewed in [112
]. Space does not permit discussion of all studies involved, but we will briefly discuss major approaches, outcomes and challenges.
Disease in which CD40:CD154 interactions play a role in pathogenesis
The majority of approaches to intervening in CD40-CD154 interactions used CD154-specific blocking mAbs. This strategy is highly efficacious in mouse models as discussed above and in [112
]. While overall benefit of blocking CD40-CD154 association is decreased when therapy is given after disease establishment, anti-CD154 therapy also prevents relapses of ongoing disease, and/or halts pathologic progression in models of RA, SLE, MS, IBD, diabetes and inflammatory heart disease (above and [112
]. In a model of pemphigus vulgaris, anti-CD154 Ab pre-treatment effectively induces tolerance to the major autoantigen, desmogelin-3. However, the treatment is ineffective in established disease [113
]. Similarly, anti-CD154 Ab treatment from birth of mice prone to develop a disorder similar to human systemic sclerosis prevents disease development [114
Although the major mechanism of anti-CD154 Ab therapy is assumed as physical blocking of CD40-CD154 interaction and preventing T cell priming, additional activities have been implicated. In the MS model EAE, anti-CD154 prevents disease development, but also blocks relapse of established disease, possibly by inhibiting Th1 differentiation and/or effector T cell CNS migration and activity [37
]. Similarly, delayed anti-CD154 treatment in mouse IBD shows significant clinical efficacy correlative with reduced cytokines, suggesting the effector phase of disease is affected [62
]. Anti-CD154 treatment may affect a small subset of CD40+ T cells implicated in pathogenesis of autoimmunity (see M.E. Munroe, this volume). Such T cells could be depleted via complement fixation and binding to FcγR on effector cells.
Despite the considerable promise shown for CD154 blocking Abs in mouse models, clinical experience has been mixed. A particular challenge has been thromboembolism [112
]. The reasons for this complication in humans have not been defined, but one significant difference is the presence of the FcγRIIA on human, but not mouse platelets [117
]. Thus, as CD154 is expressed on activated platelets [118
], anti-CD154 mAb could engage FcγRIIA on the same or adjacent platelets, causing aggregation. CD154 may also stabilize arterial thrombi by binding platelet integrins [119
The first anti-CD154 mAb used in clinical trials was humanized 5c8 Ab, ruplizumab. Ruplizumab treatment induced partial therapeutic responses in some SLE patients, but trials stopped early due to thromboses in some recipients [120
]. Both ruplizumab and a second anti-CD154 mAb, toralizumab, induced partial responses in some patients with refractory ITP, and no thrombotic complications were seen, possibly because ITP patients have low platelet numbers[122
]. However, no significant improvement was seen in a toralizumab trial of SLE patients [123
], and Crohn’s disease trials were halted after a thrombosis developed in a recipient [112
]. A third anti-CD154 mAb, ABI793, binds to a different CD154 epitope, and showed promise in primates, but thromboembolism occurred during organ transplant trials [112
]. Interestingly, this indicates that this complication occurs independently of CD154 epitope.
Given recurring concerns about thromboembolism with therapies using intact anti-CD154 mAbs, alternatives are needed to exploit the benefits of blocking CD40 signals to alleviate autoimmunity. One possibility is engineering Abs that won’t bind FcRs or activate complement (C′). As this will not allow C′-mediated T cell elimination, such Abs may not prevent transplant rejection, but may still benefit autoimmune diseases. An aglycosyl ruplizumab with decreased FcR and C′ binding cannot prevent transplant rejection in monkeys, but prolongs survival and reduces autoantibody production in mouse SLE [124
]. Aglycosyl mAbs remain effective in alleviating symptoms in mouse EAE [125
]. Another approach used blocking peptide mimics that have the functional CD40 binding site but block association of CD154 [126
]. Some of these peptides have efficacy in relieving symptoms of mouse EAE [126
], but only at high concentrations [126
], a challenge for practical applications.
A promising alternative uses mAbs against CD40, rather than CD154. While many anti-CD40 mAbs exist, and vary considerably in specific epitope recognition and binding affinities, no consistent correlations have emerged between affinity, ability to block CD154 binding, and agonistic activity (reviewed in [112
]. However, several mAbs antagonistic to CD40 activation signals show promising initial results as autoimmune disease treatments. The human anti-CD40 mAb HCD122 blocks and competes with CD154 for binding to CD40, but does not itself induce CD40 signaling, and mediates antibody-dependent cellular cytotoxicity against CD40+
myeloma cells [128
]. However, it isn’t clear if this mAb would be useful in autoimmune disease therapy. Another humanized anti-human CD40 antagonist mAb, ch5D12, showed promise in a phase I/IIa Crohn’s disease study [69
]. Thus, future clinical development of antagonistic anti-CD40 mAbs is desirable.
The preceding overview emphasizes the multiple ways in which CD40:CD154 interactions, critical for normal adaptive immunity, can also play important roles in the establishment and pathogenesis of a wide variety of autoimmune disease. New ways of intervention that spare normal immune function while blocking damaging effects of CD40 signaling are a key future goal.