Complement-Mediated Microvascular Injury Leads to Chronic Rejection

Abstract

Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant ischemia, can lead to tissue infarction and airway fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). BOS is the major obstacle to lung transplant success and affects up to 60% of patients surviving 5 years. The role of complement in causing acute microvascular loss and ischemia during rejection has recently been examined using the mouse orthotopic tracheal transplantation; this is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway fibrosis in rejecting tracheal allografts, C3 deposits on the vascular endothelium just as tissue hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days. Complement deficiency and complement inhibition lead to markedly improved tissue oxygenation in transplants, diminished airway remodeling, and accelerated vascular repair. CD4+ T cells and antibody-dependent complement activity independently mediate vascular destruction and sustained tissue ischemia during acute rejection. Consequently, interceding against complement-mediated microvascular injury with adjunctive therapy during acute rejection episodes, in addition to standard immunosuppression which targets CD4+ T cells, may help prevent the subsequent development of chronic rejection.

Untitled

“…Chronic rejection is characterized by induction of fibroblast proliferation, pleomorphic effects (such as proliferation of smooth muscles) by some cytokines, maturation of B-cells and antibody synthesis by IL-4 [26][27][28]. Moreover, fibrosis formation is very common with chronic rejection due to the activation of the tissue repair process [29,30]. Immuno suppressants are administered to transplant recipients to hinder the immune response and allow for survival of the transplanted tissue [31] Although immune suppressants are extremely necessary, they also carry some adverse effects ( Table 1) [32], immune suppression reduces the patient's ability to fight against communicable diseases, enhances the risk of metabolic complications and may elicit toxicity to the immunosuppressive drug [31].…”

T regulatory Cell-mediated Immunotherapy for Solid Organ Transplantation: A Clinical Perspective

“…Likewise, most immunotherapies for organ transplantation face the challenges of achieving enough immunosuppression to prevent organ rejection or limit auto reactivity without impairing the host's ability to guard against opportunistic infections, and malignancies. Immune system defends the host from a broad range of pathogens and foreign tissue antigens while preventing unwarranted and exaggerated immune reactions that would be deleterious to the host tissue (2)(3)(4). During an immune response, T cells, B cells, which are characterized by a broad range in antigen recognition, high specificity, strong effector response, and long-term immunologic memory, modulate an effective immune response against a foreign tissue antigens (5) (6).…”

Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective

“…The complement system is an effector of innate immune response with the ability to enhance antibody-mediated removal of foreign antigens and cellular debris, as well as the ability to initiate local inflammatory responses [1,2] that destroy pathogens and recruit cellular repair mechanisms. Angiogenesis is an example of the reparative role of immune inflammation with pathological significance in ischaemic and inflammatory diseases, including coronary artery disease, acute myocardial infarction and transplant allograft rejection [3,4].…”

“…The C3b molecule then combines with C3 convertase to form the C4bC2aC3b complex in classical and lectin pathways, and to the formation of the C3bBbC3b complex in the alternate pathway. Both C4bC2aC3b and C3bBbC3b complexes are C5 convertases, which cleave C5 into C5a and C5b [2,20,21]. The generated C5a can then function as a potent anaphylatoxin at the site of production, while C5b participates in the assembly of the membrane attack complex (C5b-9 or MAC) [22].…”