Cytokines allograft rejection

Benjamin LC, Allan JS, Madsen JC. 2002. Cytokines in immunity and allograft rejection. Crit Rev Immunol. 22 269-279. 

Lattmann T, Hein M, HOrber S, Ortmann J, et al. 2005. Activation of pro-inflammatory and antiinflammatory cytokines in host organs during chronic allograft rejection Role of endothelin receptor signaling. Am J Transplant. 5 1042-1049. 

As described, IL-2 binds rapidly to its cellular receptor, which may then be shed from the cell surface into the tissue fluid and from there to the peripheral blood. IL-2 itself has a much shorter half-life than that of the shed receptor. The presence of the soluble receptor is thus a better measure of IL-2 activity than levels of the cytokine itself (R30). IL-2 activity has been a prime target for research into better markers of rejection as it is a key component in T-cell priming for allograft rejection and could be expected to change at a very early stage. 

Probably the best studied mAb to CDS in experimental models is the hamster anti-murine CDS mAb 145-2C11 which recognizes an epitope of the epsilon chain in the CDS complex (29). This mAb is a potent immunosuppressive agent in vivo capable of delaying skin allograft rejection to a mean of 32-34 days compared to untreated controls (30). Administration of the first dose of mAb triggers a cytokine release syndrome characterized by the presence of TNF-a. 

The receptor for interleukin-2 consists of a molecular complex of three chains termed a (CD25), 8 (CD122), and y (CD132). The a chain is specific for the IL-2 receptor complex whilst the p and y chains are also found in the receptors for other cytokines. The IL-2Ra subunit is only expressed on activated and not resting T cells. Monoclonal antibodies targeting the a subunit can therefore selectively impair T lymphocytes participating in allograft rejection. 

Inhibition of immunomodulatory cytokines (Fig. 1) Anti-T-cell receptor antibodies Muromonab (OKT3, Orthoclone ) binds to the CD3 complex of the T-cell receptor and induces depletion of T-lymphocytes. It is applied to prevent acute rejection of kidney, liver, and heart allografts. Rapid side effects (within 30-60 min) include a cytokine release syndrome with fever, flu-like symptoms, and shock. Late side effects include an increased risk of viral and bacterial infections and an increased incidence of lymphproliferative diseases due to immunosuppression. 

---