Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection.
BACKGROUND
Chronic human lung allograft rejection, represented by bronchiolitis obliterans syndrome (BOS), is the single most important factor that limits the long-term survival following lung transplantation (LT). However, the pathogenesis of BOS remains unclear. We hypothesized that the early posttransplant inflammation would promote the development of donor anti-human leukocyte antigen (HLA) alloimmunity and predispose to BOS.


METHODS
Serum levels of interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, IP-10, MIG, MCP-1, MIP-1alpha, MIP-1beta, RANTES, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, granulocyte-macrophage colony-stimulating factor, IL-1Ralpha, and IL-2R were serially analyzed in 31 BOS+ and matched 31 BOS- patients using quantitative multiplex bead immunoassays. Donor-specific HLA class II cellular immunity was analyzed using enzyme-linked immunospot (ELISPOT) by testing recipient peripheral blood mononuclear cells against mismatched donor HLA-DR peptides. Anti-HLA class II antibodies were monitored using flow panel reactive antibodies.


RESULTS
There was early posttransplant elevation in basal serum levels of proinflammatory chemokines IP-10 and MCP-1 and Th1-cytokines IL-1beta, IL-2, IL-12, and IL-15 in BOS+ patients, compared to BOS- and normal subjects. In addition, a threefold decline in IL-10 levels was found during BOS development. BOS+ patients revealed increased development of HLA class II alloantibodies and Th1-predominant donor-specific cellular immunity with high frequency of IFN-gamma and low IL-5 producing T-cells.


CONCLUSIONS
Early posttransplant elevation of proinflammatory mediators is associated with alloimmunity and chronic human lung allograft rejection.
Bharat
Ankit
A
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Narayanan
Kishore
K
Street
Tyler
T
Fields
Ryan C
RC
Steward
Nancy
N
Aloush
Aviva
A
Meyers
Brian
B
Schuessler
Richard
R
Trulock
Elbert P
EP
Patterson
G Alexander
GA
Mohanakumar
Thalachallour
T
D001989:Bronchiolitis Obliterans / Q000097:blood / Q000276:immunology; D002908:Chronic Disease; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D008168:Lung; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018417:Th1 Cells / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators