Laminins are heterotrimeric glycopeptides composed of an α (1–5), β (1–3), and γ (1–3) chain and constitute one of the major structural proteins of the basal membrane in vessels.1 Laminin ablation in mice is usually lethal because of its role in embryonic development and vascular integrity.2 In transplantation, the role of 2 laminin isoforms, α4β1γ1 (411) and α5β1γ1 (511), is increasingly being recognized as a potential new target to promote organ tolerance.
Laminin expression in the cortical ridge and high endothelial venules of lymphoid organs and within the graft is a dynamic process that is controlled by several factors, including cytokines, proteases, and growth factors.2 Thus, the ratio between laminin 511 and 411 expressions in lymph nodes can be modulated after induction of immunity or tolerance (Figure 1). In the present study,3 immunity and inflammation were modeled using emulsified complete freund adjuvant subcutaneous injection and dextran sulfate sodium-induced inflammatory colitis. This inflammatory state was associated with a high laminin α5 expression. In contrast, a tolerogenic environment based on donor lymphocyte infusion and anti-CD40L mAb administration was associated with a low laminin α5/α4 expression ratio. These dynamic changes were observed within 5 hours of injection and are likely to participate in the remodeling of the extracellular matrix of the lymph node. These data suggest that laminin regulation may depend not only on protein synthesis but also on cell surface polymerization, laminin degradation, and/or recruitment of laminin-positive cells.
Laminins interfere with many immune cells that regulate not only trafficking but also activation and differentiation of T cells. Thus, autoimmune disorders such as cicatricial pemphigoid, lupus erythematosus, or autoimmune myocarditis are associated with autoantibodies targeting laminins.1,4-7 Laminins have pleiotropic numbers of receptors expressed on a variety of cells that they interact with; this includes integrins and dystroglycan (DG) receptors. Controversial data exist on the respective role of laminin 411 and 511 on T cells transmigration, although the literature agrees that the interaction of α5 laminin depends of the α6 integrin receptors in T cells.1 On one hand, laminin 511 act as a migration adhesion and migration-promoting isoform for lymphocytes into lymphoid organs, and on the other hand, laminin 511 selectively inhibits T lymphocyte extravasation into the brain.8,9 In the present article, Simon and colleagues explored the activation, differentiation, and proliferation of T cells upon exposure to laminin 511 and 411, which happen downstream to T-cell adhesion and migration (Figure 1).3 Laminin 511 actively acts on Th1/2/17 polarization while inhibiting regulatory T cells. Importantly, blocking α6-integrin reduced CD4 T cells proliferation in vivo, demonstrating that this receptor acts as a costimulatory molecule in T cells. In contrast, the inhibitory effect of laminin 411 on T cells could not be blocked using multiple antibodies. This is potentially due to the receptors on lymphocytes being redundant, of low affinity, or simply unknown, as suggested by the authors. This differential regulation of laminin was confirmed in vivo using a heterotopic allogeneic heart transplant model in mice. Thus, the combination of anti-α6 integrin or anti-αDG with anti-CD40L significantly prolongs heterotopic heart allograft survival in mice. Importantly, the anti-α6 integrin alone only slightly prolonged heterotopic heart allograft survival from a median survival of 7–10 days. A similar, nonsignificant increase was observed with anti-αDG. These data reinforce previous results showing that blocking laminin α5 or alternatively laminin α4 results in increased or reduced heart allograft survival, respectively.10
The presented experiments are very promising and could potentially introduce a new generation of immunosuppressive drugs. Before starting to test new drugs/antibodies in patients, additional preclinical experiments are necessary. Investigators will need to test the potency of the laminin 511-α6 integrin axis blockade with a defined course of tacrolimus and/or mycophenolate to see whether these blocking antibodies can induce tolerance in a model close to the clinical setting. A way of testing this will be to perform allotransplantation experiments under standard immunosuppression in conditional knockouts animals for laminins α5 and α4. The type and site of transplantation could play an important role owing to differences in terms of specific graft α4:5 laminin ratio, tolerance induction success rates,11 and angiogenesis dependency.12 Laminin 511-α6 integrin axis blockade in islet or skin transplant models could potentially address these questions. Since the expression of laminins is dynamic, it would also be of interest to better understand how the α5/α4 laminin ratio evolves in the graft and draining lymphoid organs over time, including in the context of human transplants. There might be a rationale to use this kind of drugs for induction rather than maintenance therapy. Finally, novel routes of drug administration could be explored. If one could block or decrease α5 laminin expression, such drug could be perfused within the graft before transplantation and eventually diffuse secondarily in draining lymph nodes.
Overall, this work is pointing out new directions in the role of extracellular matrix and laminins in transplantation and opening way for new strategies for immunosuppression.
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