Tolerance Induced by Apoptotic Antigen-Coupled Leukocytes Is Induced by PD-L1+ and IL-10–Producing Splenic Macrophages and Maintained by T Regulatory Cells

Abstract

Antigen-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide antigens linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-SP) has been demonstrated to be a highly efficient method for inducing peripheral, antigen-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. Here, we show that apoptotic Ag-SP accumulate in the splenic marginal zone where their uptake by F4/80+ macrophages induces production of IL-10 which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 which is essential for Ag-SP tolerance induction. Ag-SP infusion also induces Tregs which are dispensable for tolerance induction, but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. We show for the first time that tolerance results from the synergistic effects of two distinct mechanisms – PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of Tregs. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting MS.

Harnessing Nanoparticles for Immune Modulation

“…The use of apoptotic cells to induce tolerance was uncovered originally in 1979 [79] and has shown promise in an early clinical study [80], However, the use of cells has numerous manufacturing, cost, and patient accessibility issues. The serendipitous discovery that negatively charged NPs target specific scavenger receptors and localize to the same regions of the spleen, similar to apoptotic cells, catalyzed the development of a synthetic cell replacement that could carry antigen for immune tolerance induction [6,8,81]. Subsequently, several NP-based approaches for the induction of immune tolerance that function via alternative mechanisms have emerged.…”

“…Tolerogenic IMPs (TIMPs) were designed to take advantage of the MARCO-targeting ability of highly negatively charged NPs [8,89]. The intravenous administration of antigen-encapsulated IMPs results in biodistribution similar to that of apoptotic debris [6,81], with particles homing to MARCO+ macrophages in the liver and spleen (Figure 2) [6,8,9,81]. More importantly, one course of TIMPs results in tolerance induction through T cell anergy and the parallel induction of Tregs [90].…”

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

“…Strategies to induce tolerance include conjugating antigen to splenocytes [8], immature dendritic cells (DC) [9,10], or synthetic microparticles [11,12], oral tolerance [13], gene therapy [14] or co-treatment with immunosuppressive drugs, such as methotrexate [15]. Recently, it has been reported that systemic co-administration of rapamycin, a immunosuppressant drug commonly used to prevent transplant rejection, prevented immune response and induced tolerance to FIX and FVIII in mouse models of hemophilia A and B, respectively [29,30].…”

Bowman lecture on the role of inflammation in degenerative disease of the eye

“…For instance, the scavenger role of splenic macrophages for aged red cells is known to every medical student, while the recent tolerising role of macrophages such as the F4/80 þ macrophages in the mouse has been revealed. 73 The new and interesting information on heterogeneity in macrophages, some with inflammatory functions, others with anti-inflammatory roles, is highly relevant to disease in the eye, such as AMD, diabetes, and uveitis and probably many other conditions associated with the degenerative diseases of ageing. The balance of outcome seems to depend on whether the effects of low level chronic inflammation are more or less deleterious to the host compared with the potentially destructive effects of the healing response, which are more than amply played out in the retina.…”