Thursday, February 18, 2016

pMHC tetramer-coated nanoparticles treat autoimmune conditions in mice

This week Nature published "figure-dense" paper showing that nanoparticles coated with auto-antigen+MHC complexes (pMHC) could treat spontaneous or experimentally-induced autoimmune diseases in mice. In fact, this study contains so many experimental results it should have been published in two part, in my view. I will try to condense its basic findings in few paragraphs and provide its interpretation below.

Non-obese diabetic (NOD) mice spontaneously develop [autoimmune] diabetes. Part of T cells that infiltrate and damage β cells in NOD mice express T-cell receptor (TCR) resembling diabetogenic BDC2.5-specific TCR that can be recognized by pMHC–2.5mi/IAg7 tetramers. When the authors injected nanoparticles (dextran-coated or pegylated iron oxide NPs) coated with 2.5mi/IAg7 tetramers (pMHC–NP) it induced expansion of cognate CD4+ T cells in blood and spleens of NOD mice. These cells had a memory-like (CD44hiCD62Llow) FOXP3− TR1-like phenotype.


These "activated/experienced" CD4+ TR1 cells from donor mice treated with pMHC–2.5mi/IAg7-NPs suppressed diabetes development in T-cell-reconstituted NOD-scid hosts upon adoptive transfer. This effect of TR1 cells was augmented by treating hosts with pMHC–NPs.


Moreover, 90–100% of the already diabetic mice that received nanoparticles coated with β cell antigens, 2.5mi/IAg7, IGRP4–22/IAg7 or IGRP128–145/IAg7, reverted to stable normoglycaemia.


Of note, treatment withdrawal resulted in loss of the normoglycaemic state in 25–60% of mice, in association with the loss of the tetramer+CD4+ T-cell pools. In other words, these data suggest that almost half of treated diabetic mice maintained normoglycaemic state after 5 weeks of treatment.


Beyond diabetes, the authors showed that nanoparticles coated with myelin oligodendrocyte glycoprotein, pMOG38–49/IAb–NP, dampended progression of experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis), when given on day 14 after immunization and even restored motor function in paralytic mice when given on day 21.


Similar therapeutic effects were seen in 3rd autoimmune disease model, collagen-induced arthritis (CIA). HLA-DR4-IE-transgenic mice receiving nanoparticles displaying mouse collagen (mCII)259–273/DR4-IE showed reduced joint inflammation. In all these models, pMHC–NPs effect was antigen-specific.

Indeed, the effects of pMHC–NP therapy were not associated with impaired systemic immunity because pMHC–NP-treated mice showed unimpaired anti-viral immunity and mounted antibodies against an exogenous antigen as efficiently as control mice.

Interestingly, pMHC–NPs could not expand tetramer+ T cells in non-diabetic control mice which harbor mostly naive T cells. Further experiments confirmed that therapeutic effect of pMHC–NP required presence of "experienced" T cells. For example, whereas pMHC–NP therapy afforded 100% diabetes protection to T-cell-reconstituted NOD-scid hosts bearing memory BDC2.5 T cells, such therapy was inconsequential in hosts receiving naive BDC2.5 T cells.


The role of "experienced", but not naive T cells, in therapeutic effect of pMHC–NP was also supported by observation that whereas diabetic NOD G6pc2−/− mice (which lack IGRP antigen and corresponding memory/experienced T cells, but most likely harbor IGRP4–22 specific [aka, nonself-specific] naive T cells) responded to 2.5mi/IAg7–NPs like wild-type NOD mice, they did not respond to IGRP4–22/IAg7–NPs.


At molecular level, the authors showed blockade of IL-10, TGF-β and IL-21R (but not IFNγ) abrogated the anti-diabetogenic properties of 2.5mi/IAg7–NPs or IGRP4–22/IAg7–NPs in diabetic NOD mice.

However, to make things more complicated, the authors also showed that the development of the TR1 precursors and/ or TR1-like cells that expand in response to pMHC–NP therapy required IFNγ in addition to IL-10 in pre-diabetic NOD mice.

Finally, the authors found that at the cellular level, pMHC–NP treated NOD mice harbored increased numbers of so called regulatory B cells, BREG cells (but only in pancreatic lymph nodes, PLNs). These BREG cells were producing IL-10 in response to lipopolysaccharide (LPS). In vivo, these B cells suppressed diabetes development in T-cell-reconstituted NOD-scid hosts as compared to PLN B cells from control mice (and worked together with TR1 cells). The role of BREG cells was supported by observation that treatment of newly diabetic NOD mice with a B-cell depleting anti-CD20 mAb abrogated the anti-diabetogenic activity of 2.5mi/IAg7–NPs (see above).




In summary, this study suggests that when injected into mice these pMHC–nanoparticles expand antigen-specific and antigen-experienced T cells with regulatory properties. These TR1 work with BREG cells to block the chain of events that perpetuates autoimmune cycle. 

David Usharauli


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