Can cells and biomaterials in therapeutic medicine be shielded from innate immune recognition?

Abstract

Biomaterials (e.g. polymers, metals, or ceramics), cell and cell cluster (e.g. pancreatic islets) transplantation are beginning to offer novel treatment modalities for some otherwise intractable diseases. The innate immune system is involved in incompatibility reactions that occur when biomaterials or cells are introduced into the blood circulation. In particular, the complement, coagulation and contact systems are involved in the recognition of biomaterials and cells, eliciting activation of platelets and leukocytes. Such treatments are associated with anaphylactoid and thrombotic reactions, inflammation, and rejection of biomaterials and cells, leading to treatment failures and adverse reactions. We discuss here the new technologies that are being developed to shield the biomaterial and cell surfaces from recognition by the innate immune system.

Figure 1

Incompatibility reactions triggered by innate immune responses to altered-self and non-self structures on biomaterials, cells, and cell clusters for therapeutic use. Upon exposure to blood, recognition molecules belonging to different cascade systems target altered-self and non-self structures on biomaterials and cells. Factor (F) VII, fibrinogen, and Tissue Factor (TF) are “recognition/trigger” molecules in the coagulation system; FXII and High Molecular Weight Kininogen (HMWK) in the contact system; and C1q, mannose-binding lectin (MBL), and properdin in the complement system. The activation of each cascade system triggers amplification reactions. Activation of the coagulation cascade leads to the generation of thrombin from prothrombin. Further activation of the contact system elicits generation of the potent vasoactive peptide bradykinin from HMWK. In the complement cascade, there is a powerful amplification of C3 that initiates generation of the anaphylatoxins C3a and C5a, as well as the lytic C5b-9 complex. The generated activation products in turn trigger activation of platelets, polymorphonuclear leukocytes (PMNs), and moncytes/macrophages, which result in thrombotic and inflammatory reactions. These adverse events, together with complement-mediated cell lysis, and coagulation-mediated sequestration may lead to rejection or serious damage to the biomaterial or transplanted cells.

Figure 2

Examples of biomaterials and administered therapeutic cells and cell clusters, that come into direct contact with patient blood. i) During cardiopulmonary bypass, blood is transferred from the patient to an oxygenator where blood gases are exchanged and is thereafter returned to the patient. Thrombotic reactions can potentially occur while blood is passing through the extrcorporeal oxygenator and return clots to the patient bloodstream ii) Heart valves composed of various non-self materials can be in contact with blood for years. iii) Plasmapheresis is a procedure where plasma is prepared by centrifugation and/or filtration from the patient’s blood. The plasma may either be discarded or processed in an affinity column before it is returned to the patient. Plasma can also be drawn from blood donors for therapeutic use. iv) During hemodialysis, the patient’s blood is exposed to a dialysis membrane for many hours several times a week. v) Transplantation of hematopoetic stem cells and vi) mesenchymal stem cells is performed by infusing the cells into the blood using a central venous catheter. vii) Islets of Langerhans and viii) hepatocytes are prepared from pancreas and liver, respectively, using proteolytic enzymes and are then infused into the portal vein of the recipient.

Figure 3

Different strategies to shield off the surface of biomaterials and cells against innate immune attack. A) Treatment of biomaterials and cells that gives passive protection against innate immune system attack. Left: polyethylene glycol (PEG) coating (green zigzag); middle: Hydrogels consisting of PEG that has been polymerized with a cross-linking agent (red bars); right: a complex between alginate (blue) and cations (red circles). B) Heparin coating consisting of macromolecular complexes of multiple heparin chains (red) covalently bound to a polycarbon backbone (black). C) Different methods for binding a regulatory molecule to a cell or biomaterial surface, here exemplified by the regulator of complement activation (RCA) molecule factor H, consisting of 20 short consensus repeats (SCR). Left: covalent binding using a cross-linking agent (green bar); middle: binding to end group activated Pluronic; right: adhesion of endogenous factor H from blood which binds to a specific peptide, antibody, or antibody fragment (blue “V”).