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2015 ; 116
(10
): 1670-9
Nephropedia Template TP
Shen H
; Heuzey E
; Mori DN
; Wong CK
; Colangelo CM
; Chung LM
; Bruce C
; Slizovskiy IB
; Booth CJ
; Kreisel D
; Goldstein DR
Circ Res
2015[May]; 116
(10
): 1670-9
PMID25801896
show ga
RATIONALE: Early graft inflammation enhances both acute and chronic rejection of
heart transplants, but it is unclear how this inflammation is initiated.
OBJECTIVE: To identify specific inflammatory modulators and determine their
underlying molecular mechanisms after cardiac transplantation. METHODS AND
RESULTS: We used a murine heterotopic cardiac transplant model to identify
inflammatory modulators of early graft inflammation. Unbiased mass spectrometric
analysis of cardiac tissue before and ?72 hours after transplantation revealed
that 22 proteins including haptoglobin, a known antioxidant, are significantly
upregulated in our grafts. Through the use of haptoglobin-deficient mice, we show
that 80% of haptoglobin-deficient recipients treated with perioperative
administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited
>100-day survival of full major histocompatibility complex mismatched allografts,
whereas all similarly treated wild-type recipients rejected their transplants by
21 days after transplantation. We found that haptoglobin modifies the
intra-allograft inflammatory milieu by enhancing levels of the inflammatory
cytokine interleukin-6 and the chemokine MIP-2 (macrophage inflammatory protein
2) but impair levels of the immunosuppressive cytokine interleukin-10.
Haptoglobin also enhances dendritic cell graft recruitment and augments antidonor
T-cell responses. Moreover, we confirmed that the protein is present in human
cardiac allograft specimens undergoing acute graft rejection. CONCLUSIONS: Our
findings provide new insights into the mechanisms of inflammation after cardiac
transplantation and suggest that, in contrast to its prior reported antioxidant
function in vascular inflammation, haptoglobin is an enhancer of inflammation
after cardiac transplantation. Haptoglobin may also be a key component in other
sterile inflammatory conditions.
|Abatacept
[MESH]
|Animals
[MESH]
|Cell Proliferation
[MESH]
|Cells, Cultured
[MESH]
|Chemokine CXCL2/metabolism
[MESH]
|Dendritic Cells/immunology/metabolism
[MESH]
|Disease Models, Animal
[MESH]
|Female
[MESH]
|Graft Rejection/blood/genetics/*immunology/pathology/prevention & control
[MESH]
free
free
free
