Acute antibody-mediated complement activation mediates lysis of pancreatic islets cells and may cause tissue loss in clinical islet transplantation.
BACKGROUND
Clinical islet transplantation is associated with loss of transplanted islets necessitating tissue from more than one donor to obtain insulin independence. The instant blood-mediated inflammatory reaction (IBMIR) is one explanation to the tissue loss. Complement activation is an important cytotoxic component of the IBMIR, and in the present study, we have investigated this component in detail.


METHODS
Isolated human islets were analyzed by large particle flow cytometry and confocal microscopy after incubation in human ABO-compatible hirudin-plasma.


RESULTS
After incubation in plasma, the islets bound IgG and IgM, CIq, C4, C3 and C9. The binding of C3b/iC3b was evident already after 5 min. The binding of C3b/iC3b and the generation of C3a and sC5b-9 were inhibited by the complement inhibitor Compstatin. Lysis as reflected by propidium iodide (PI) staining and release of C-peptide was also inhibited by Compstatin. There were significant correlations between IgM/IgG versus C3b/iC3b and between sC5b-9 and C-peptide.


CONCLUSIONS
The conclusion is that complement is activated by natural IgG and IgM antibodies already after 5 min. The complement activation leads to lysis of cells of the pancreatic islets. This very rapid reaction may be an essential entity of the damage induced by the IBMIR in clinical islet transplantation.
Tjernberg
Jenny
J
Department of Oncology, Rudbeck Laboratory, Uppsala, Sweden.
Ekdahl
Kristina N
KN
Lambris
John D
JD
Korsgren
Olle
O
Nilsson
Bo
B
D000906:Antibodies / Q000276:immunology*; D002096:C-Peptide / Q000378:metabolism; D003167:Complement Activation; D003179:Complement C3b / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology
D000906:Antibodies; D002096:C-Peptide; D010456:Peptides, Cyclic; C111828:compstatin; D003179:Complement C3b