Editors' ChoiceOrgan Transplantation

IgM Antibodies to the Rescue!

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Science Translational Medicine  22 Feb 2012:
Vol. 4, Issue 122, pp. 122ec33
DOI: 10.1126/scitranslmed.3003873

Solid organ transplantation is a marvel of modern medicine; tens of thousands of patients await organs. Although the survival rate for transplant recipients has substantially improved over the past several decades, organ rejection remains a challenge. Transplant rejection mediated by alloreactive T cells, which react against tissue from a genetically distinct donor, and reperfusion injury, which is tissue damage that occurs when blood returns after oxygen deprivation, are two major mechanisms of long-term graft failure. A class of immunoglobulin M (IgM) autoantibodies of unknown function, which bind to leukocyte antigens and increase during inflammatory conditions, might help prevent such failure.

Because patients with high blood levels of such IgM antibodies show better transplant outcomes than those without, Lobo et al. examined whether these antibodies might protect against transplant rejection in mice. The authors transplanted genetically mismatched hearts into either wild-type or IgM knockout (KO) mice, which lack such antibodies, and found that allograft rejection was more rapid and severe in the KO strain. This rejection was apparently not due to a defect in immune-suppressing regulatory T cells (Treg cells), because they were present at normal levels and retained their suppressive capacity in IgM KO mice. Three doses of IgM, administered to mice after transplant, protected against rejection of the genetically incompatible hearts, suggesting the therapeutic potential of IgM. Furthermore, anti-leukocyte IgM protected wild-type mice against reperfusion injury in the kidney, decreasing inflammatory cytokines interleukin 17 and interferon γ as well as chemokines important for leukocyte migration.

In vitro, anti-leukocyte IgM reduced alloreactive T cell proliferation and production of interferon γ, which is implicated in organ rejection. IgM also decreased the capacity of T cells, including Treg cells, for differentiating into TH17 cells, which act in transplant rejection. Last, the authors showed that IgM might decrease innate immune activation by inhibiting Toll-like receptor 4.

In this intriguing study, Lobo et al. show that IgM might protect against transplant rejection by acting on both innate and adaptive immunity. Their work should spur further research into the therapeutic potential of IgM administration in transplant patients.

P. I. Lobo et al., Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17. J. Immunol. 188, 1675–1685 (2012). [Abstract]

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