Lacto-N-fucopentaose III, a pentasaccharide, prolongs heart transplant survival.
BACKGROUND
Lacto-N-fucopentaose III (LNFPIII) is a pentasaccharide containing the Lewis(x) trisaccharide that is found on schistosome eggs and in breast milk. LNFPIII conjugates suppress host immune responses and have therapeutic efficacy in mouse models of psoriasis and type 1 diabetes.


METHODS
We used nonvascularized neonatal ear-heart transplantation and heterotopic vascularized heart transplantation models to evaluate immunosuppressive effects of LNFPIII and subsequently analyzed the mechanism.


RESULTS
We found that administration of LNFPIII conjugates prolonged median graft survival by 80% when 1-day-old DBA/2 hearts were transplanted into ears of B6 mice. A similar graft prolongation was observed in a fully vascularized heterotopic heart transplantation model (DBA/2 into B6), No prolongation was observed with carrier protein (human serum albumin [HSA] or dextran) alone. We found increased programmed death ligand 1 (PD-L1) expression on F4/80 macrophages, CD4+ T cells, and CD11b+ CD11c+ (myeloid) dendritic cells, and increased arginase1 and Ym1 expression, typical of alternatively activated macrophages, in the draining (cervical) lymph node cells. We found accumulation of Foxp3+ regulatory T cells (Tregs) in the lymph nodes draining donor hearts, suggesting a possible role of Treg induction in graft prolongation. Anti-PD-L1 antibody treatment abrogated LNFPIII-mediated the graft survival benefit and Treg accumulation. LNFPIII-treated macrophages had increased PD-L1 expression and significantly prolonged DBA/2 allograft survival when injected intraperitoneally into B6 recipient mice.


CONCLUSIONS
LNFPIII prolongs fully allogeneic graft survival in both vascularized and nonvascularized allograft transplantation models. The mechanism of graft prolongation seems to involve both alternatively activated PDL-1 macrophages and recruitment of Foxp3+ Treg cells.
Dutta
Partha
P
Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Hullett
Debra A
DA
Roenneburg
Drew A
DA
Torrealba
Jose R
JR
Sollinger
Hans W
HW
Harn
Donald A
DA
Burlingham
William J
WJ
D000606:Amino Sugars / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology; D011134:Polysaccharides / Q000494:pharmacology*; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous
D000606:Amino Sugars; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D010455:Peptides; D011134:Polysaccharides; C434666:lacto-N-fucopentaose III