Anti-CD45RB antibody deters xenograft rejection by modulating T cell priming and homing.
Pancreatic islet xenotransplantation has been advocated as a way of overcoming the shortage of human donor tissue for the treatment of type 1 diabetes. However, the potent immune response against xenografts is a major barrier to their use. We show that a short course of the anti-CD45RB antibody, MB23G2, prolongs survival of fetal pig pancreas grafts in mice. To investigate this effect further we used an i.p. xenograft model in which both donor pig cells and host inflammatory cells can be expediently recovered and analyzed. Graft prolongation was associated with reduced T cell and macrophage infiltration, and reduced production of both T(h)1 and T(h)2 cytokines at the graft site. Graft survival was further increased and T cell infiltration further reduced by combining anti-CD45RB antibody with co-stimulation blockade. The primary effect of anti-CD45RB antibody may be on CD4 T cells, in keeping with the marked reduction in T cell cytokine production in both spleen and graft sites. This concurs with previous studies in allogeneic models that indicate that this antibody perturbs T cell responses by modifying signaling via the TCR. In addition, anti-CD45RB treatment led to reduced expression of LFA-1 and CD62 ligand (CD62L) on CD4 T cells, independent of antigenic challenge. LFA-1 may enhance co-stimulation, and both LFA-1 and CD62L are involved in T cell trafficking. Their reduced expression provides an explanation why the T cell pool is reduced in lymph nodes. We conclude that modulation of inflammation against xenografts by anti-CD45RB antibody is due to effects on both T cell priming and trafficking.
Sutherland
Robyn M
RM
Walter and Eliza Hall Institute for Medical Research, PO The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
McKenzie
Brent S
BS
Zhan
Yifan
Y
Corbett
Alexandra J
AJ
Fox-Marsh
Annette
A
Georgiou
Harry M
HM
Harrison
Leonard C
LC
Lew
Andrew M
AM
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D016332:Fetal Tissue Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D018796:Immunoconjugates; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D019041:L-Selectin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D034421:Sus scrofa; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D016169:Lymphocyte Function-Associated Antigen-1; D019041:L-Selectin; D000069594:Abatacept; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1