Costimulatory Blockade
Anti-CTLA4 Therapy
Engagement of CD28 on naive T cells by either B7-1 or B7-2 ligands on APCs provides a potent costimulatory signal to T cells. Blockade of CD28 costimulation can be strongly immunosuppressive, preventing induction of pathogenic T-cell responses in autoimmune disease models and allowing for prolonged acceptance of allografts in models of organ transplantation.[6,7] CTLA4 is a homolog of CD28, but it exerts an inhibitory signal. CTLA4 binds to B7-1 or B7-2 molecules with much higher avidity, rendering T cells less sensitive to stimulation by APCs and limiting their proliferative responses.
Some studies have shown that neither CYP alone, nor combining CTLA4 with anti-CD40 ligand (CD40L), was effective at inducing remission in proteinuric NZB/WF 1 mice. However, complete proteinuria remission occurred in 60–80% of the animals when given triple therapy,[8,9] and once relapse occurred, remission could be reinduced in 50% of mice with a second course of triple therapy.
Anti-CD40–CD40L Therapy
A potential role of CD40–CD154 interactions has been established for several autoimmune diseases, including SLE, LN, collagen-induced arthritis and multiple sclerosis. In addition, some single nucleotide polymorphisms in the CD40 region have been associated with SLE.[10] The CD40–CD40L pair belongs to the TNF/TNF receptor superfamily emerging as an attractive target for modulation of autoimmune diseases and transplant tolerance. The costimulatory molecule CD154 is expressed predominantly on activated CD4 T cells. CD40, the receptor for CD154, is constitutively expressed on B cells. The interaction of T-cell CD40L and CD40 expressed on B cells plays a central role in humoral immune responses and is required for effective activation of both T and B cells, and stimulates B-cell proliferation, clonal expansion, differentiation of B cells into plasma cells, isotype switching, development of germinal centers, and immunologic memory.[11]
Disruption of CD40 signaling offers the potential of being therapeutically useful in autoimmune inflammatory disorders. Davidson et al. evaluated the effect of an anti-CD40L antibody in a NZB/WF 1 mouse model, initiating the therapy at 19–21 weeks, when the mice had not yet developed a significant degree of antibodies against DNA, or at 26 weeks of age, when those antibodies are already present.[9] All protocols resulted in a delayed onset of SLE but treatment was much less effective in mice with high anti-DNA antibodies titer or with established nephritis. Anti-CD40L therapy at 26 weeks was effective if given in higher and more frequent doses.
CD40–CD40L interactions play an important role in promoting pathogenic IgG autoantibody production and kidney disease. Pau et al. showed an abrogation of all IgG autoantibodies and attenuated kidney disease in NZB/W F1 CD40L−/− mice.[12] However, polyclonal B-cell activation in vivo and B-cell proliferation and class-switching in response to Toll-like receptor (TLR) ligands were preserved in the absence of CD40L in NZB mice. However, plasmacytoid DC (pDC) cell expansion and elevated B-cell-activating factor (BAFF) production were unaffected by the absence of CD40L. Blocking monoclonal antibodies against CD40L have reached the clinical testing stage with promising success, but their development has been halted due to atherothrombotic complications in study subjects.[13]
Our group has developed a siRNA molecule against murine CD40-mRNA that effectively inhibits its expression. Its intraperitoneal administration twice per week to NZB/WF 1 female mice from 6–9 months of age resulted in a reduction of anti-DNA antibody titers and histopathological renal scores compared with untreated animals. It prevented the progression of proteinuria as effectively as CYP. siRNA anti-CD40 markedly reduced interstitial CD3+ and plasma cell infiltrates, as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced. Here, we demonstrated the potency and promise of our compound for the therapeutic use of CD40 gene silencing in LN and other autoimmune disorders.[14]
Anti-PD1 Therapy
Programmed death (PD) molecules have an important role in adaptive immunity. In contrast to the positive signal of CD28/B7 or CD40–CD40L, ligation of PD1 on lymphocytes inhibits B- and T-cell proliferation and cytokine synthesis. PD1 and PDL1 interactions are essential to maintain immune tolerance and modulate activation of T cells. The effect of PD1/PDL1 modulation in LN has offered controversial results.
Anti-PD1-treated mice were protected from the onset of LN, with significantly improved survival. Anti-PD1 treatment promoted the activity of suppressive CD8+ T cells, which protected from the disease. The administration of an anti-PD1 antibody to BWF 1 mice after induction of tolerance with the tolerogenic peptide pCons abrogated tolerance, thus suggesting that tightly regulated PD1 expression is essential for the maintenance of immune tolerance.[15,16] Conversely, blocking PD-L1 using a specific antibody increased the number of CD4+PD1+ T cells in the kidney, accelerating local inflammation and enhanced serum IFN-γ, IL-10 and IgG2a dsDNA antibody levels, with an increase in mortality rate.[16]
Inducible T-cell costimulator (ICOS) is a member of the CD28 family of costimulatory molecules induced on T cells after activation, which regulates T-cell-dependent humoral immune responses.[17] Its ligand, ICOSL is constitutively expressed on B cells and inducible on monocytes and DCs at low levels.[18] Blocking the interaction between ICOS and its ligand has been beneficial for the treatment of LN in NZB/W F1 mice.[19] The combination blockade of PD1 and ICOS pathways dramatically delayed the onset of proteinuria, effectively inhibited IgG autoantibody production and significantly reduced hypercellularity and deposition of IgG in glomeruli, resulting in amelioration of LN.[20]
Immunotherapy. 2013;5(10):1089-1101. © 2013 Future Medicine Ltd.
