Exploration of helminth-derived immunoregulatory molecules as options for therapeutic intervention in allograft rejection and autoimmune disease
Johnston, Christopher John Cyril
MetadataShow full item record
Solid organ transplantation is the gold standard treatment for a variety of conditions that result in organ failure. However, despite considerable advances in clinical transplantation in recent decades, the almost ubiquitous requirement of life-long immunosuppression of transplant recipients persists and is complicated by graft loss to rejection in the long term and multiple serious adverse effects that are frequently life limiting. Helminths currently infect more than one quarter of the world’s population and it is now well established that their success as parasites is the result of active immunomodulation of the host immune response. Whilst this primarily secures ongoing survival of the parasites, in some cases helminth-induced immunomodulation can be beneficial to the infected host and is not associated with the adverse sequelae of pharmacological immunosuppression. An emerging body of evidence suggests that harmful immune responses to alloantigens can be suppressed by helminths, but little mechanistic data exists and the active immunomodulators involved have remained hitherto unidentified. The hypothesis behind this thesis is that the model intestinal nematode, Heligmosomoides polygyrus, produces immunomodulatory molecules that can suppress responses to allo- and auto-antigens in animal models of transplantation and autoimmunity, and that some of these molecules could potentially be exploited as novel therapeutic agents. Full-thickness skin grafting was performed between fully-allogeneic mouse strains (BALB/c to C57BL/6). Recipient mice infected with H. polygyrus immediately prior to transplantation showed significantly prolonged allograft survival. Likewise, protection from allograft rejection could be replicated in recipient mice in which H. polygyrus excretory-secretory products (HES) (isolated from culture of adult worms) were delivered by continuous infusion via surgically implanted osmotic minipumps. A number of potential mechanisms underlying allograft protection were identified including induction of CD4+CD25+Foxp3+ regulatory T cells (Treg) and suppression of Th1 and Th17 effector CD4+ T cell phenotypes. H. polygyrus and HES were further shown to ameliorate disease in murine (pMOG) experimental autoimmune encephalomyelitis and colitis induced by T cell transfer. In addition to expansion of Treg, H. polygyrus-mediated protection against EAE was found to be almost completely lost in IL-4 receptor deficient mice, indicating a protective role of Th2 immune responses in this context. Finally, the mechanisms of action of the newly-identified TGF-β mimic, TGM, contained within HES were investigated. Despite bearing no sequence homology or structural resemblance to TGF-β, TGM was shown to act through the TGF-β receptor complex to induce Treg in human and mouse CD4+ T cells in vitro and to suppress murine allogeneic skin graft rejection in vivo. TGM may represent the origin of a safe, effective and long-overdue novel alternative to current immunosuppression therapy.