Anti-mouse CD154 antibody treatment facilitates generation of mixed xenogeneic rat hematopoietic chimerism, prevents wasting disease and prolongs xenograft survival in mice.
BACKGROUND
The induction of xenogeneic hematopoietic chimerism is an attractive approach for overcoming the host response to xenografts, but establishing xenogeneic chimerism requires severe myeloablative conditioning of the recipient. The goal of this study was to determine if co-stimulation blockade would facilitate chimerism and xenograft tolerance in irradiation-conditioned concordant recipients.


METHODS
Wistar Furth rat bone marrow (BM) cells were injected into irradiation-conditioned C57BL/6 mice with or without co-administration of anti-mouse CD154 monoclonal antibody (mAb). Chimerism was quantified by flow cytometry, and mice were transplanted with WF rat skin and islet xenografts.


RESULTS
Blockade of CD40-CD154 interaction facilitated establishment of xenogeneic chimerism in mice conditioned with 600 cGy irradiation. Anti-CD154 mAb was not required for establishment of chimerism in mice treated with 700 cGy. However, mice irradiated with 700 cGy but not treated with anti-CD154 mAb developed a "graft-versus-host disease (GVHD)-like" wasting syndrome and died, irrespective of their development of chimerism. Xenogeneic chimeras established with irradiation and anti-CD154 mAb treatment exhibited prolonged skin and, in many cases, permanent islet xenograft survival. Chimerism was unstable and eventually lost in most recipients. Skin xenografts were rejected even in mice that remained chimeric, whereas most islet xenografts survived to the end of the observation period.


CONCLUSIONS
Blockade of host CD40-CD154 interaction facilitates the establishment of xenogeneic chimerism and prevents wasting disease and death. Chimerism permits prolonged xenograft survival, but chimerism generated in this way is unstable over time. Skin xenografts are eventually rejected, whereas most islet xenografts survive long term and perhaps permanently.
Masaki
Hideyuki
H
Division of Diabetes, University of Massachusetts Medical School, Worcester, MA, USA.
Appel
Michael C
MC
Leahy
Linda
L
Leif
Jean
J
Paquin
Linda
L
Shultz
Leonard D
LD
Mordes
John P
JP
Greiner
Dale L
DL
Rossini
Aldo A
AA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D016026:Bone Marrow Transplantation / Q000473:pathology / Q000502:physiology*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival / Q000502:physiology*; D006410:Hematopoiesis / Q000276:immunology*; D006789:Host vs Graft Reaction; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D016038:Skin Transplantation / Q000473:pathology / Q000502:physiology*; D013370:Subrenal Capsule Assay; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods; D014183:Transplantation, Heterologous / Q000502:physiology*; D014916:Whole-Body Irradiation
D000906:Antibodies; D019013:CD40 Antigens; D023201:CD40 Ligand