An anti-CD103 immunotoxin promotes long-term survival of pancreatic islet allografts.
Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103+ cells from wild type hosts. To circumvent this problem, we conjugated the nondepleting anti-CD103 monoclonal antibody, M290, to the toxin, saporin, to produce an immunotoxin (M290-SAP) that efficiently depletes CD103+ cells in vivo. Herein, we show that M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in the blood, spleen, mesenteric lymph nodes and intestinal epithelium of treated mice. We further demonstrate that M290-SAP promotes indefinite islet allograft survival in a fully MHC mismatched mouse model. The prolonged islet allograft survival resulting from M290-SAP treatment was associated with multiple effects in the host immune system including not only depletion of CD103-expressing leukocytes, but also an increase in CD4+CD25+FoxP3+ T regulatory cells and a predominance of effector-memory CD8 T cells. Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in allograft rejection.
Zhang
L
L
Division of Transplantation, Department of Surgery, The Ohio State University Medical Center, Columbus, OH, USA.
Moffatt-Bruce
S D
SD
Gaughan
A A
AA
Wang
J-J
JJ
Rajab
A
A
Hadley
G A
GA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D015703:Antigens, CD / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005260:Female; D007165:Immunosuppression Therapy; D039001:Integrin alpha Chains / Q000737:chemistry*; D016023:Integrins / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D007962:Leukocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013950:Thymus Gland / Q000166:cytology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D039001:Integrin alpha Chains; D016023:Integrins; C091367:alpha E integrins