Blockade of the CD28 and CD40 pathways result in the acceptance of pig and rat islet xenografts but not rat cardiac grafts in mice

A M Lehnert; P L Mottram; W Han; S N Walters; A T Patel; W J Hawthorne; P J Cowan; A J d'Apice; P J O'Connell

doi:10.1016/s0966-3274(01)00040-5

Blockade of the CD28 and CD40 pathways result in the acceptance of pig and rat islet xenografts but not rat cardiac grafts in mice

Transpl Immunol. 2001 Oct;9(1):51-6. doi: 10.1016/s0966-3274(01)00040-5.

Authors

A M Lehnert¹, P L Mottram, W Han, S N Walters, A T Patel, W J Hawthorne, P J Cowan, A J d'Apice, P J O'Connell

Affiliation

¹ National Pancreas Transplant Unit, University of Sydney, Westmead Hospital, NSW, Australia.

PMID: 11680572
DOI: 10.1016/s0966-3274(01)00040-5

Abstract

Previously, we demonstrated that combination CTLA4-Fc and anti-CD40L mAb treatment results in tolerance to concordant, cellular islet xenografts. The aim of this study was to determine its effectiveness in a model of fetal pig pancreas (FPP) xenotransplantation. Survival of FPP fragment grafts were compared to the survival of rat islet or cardiac xenografts following short term CTLA4-Fc and anti-CD40L mAb treatment. Rat islet and FPP fragment grafts survived long-term. However, rat cardiac grafts were rejected by 52-91 days. Both rat islet and FPP grafts showed similar histology with intact islet structures and adjacent 'nests' of lymphocytes. Concordant vascularised rat hearts showed extensive polymorphonuclear infiltrate, concentric vasculitis and a perivascular infiltrate predominantly of CD8+ T cells. This suggests that this therapy is effective for prolonging islet xenografts and demonstrates that the cellular mechanism of rejection for vascularised and non-vascularised xenografts are different.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Abatacept
Animals
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal / therapeutic use*
Antigens, CD
Antigens, Differentiation / therapeutic use*
CD28 Antigens / immunology*
CD40 Antigens / immunology*
CD40 Ligand / immunology*
CTLA-4 Antigen
Coronary Vessels / pathology
Diabetes Mellitus, Experimental / surgery
Drug Evaluation, Preclinical
Graft Rejection / immunology
Graft Rejection / pathology
Heart Transplantation / immunology*
Immunoconjugates*
Islets of Langerhans Transplantation / immunology*
Male
Mice / immunology*
Mice, Inbred CBA
Myocardium / pathology
Neutrophils / immunology
Organ Specificity
Pancreas / blood supply
Pancreas / embryology
Rats / immunology*
Rats, Inbred Strains
Species Specificity
Swine / immunology*
T-Lymphocytes, Cytotoxic / immunology
Transplantation, Heterologous / immunology*
Vasculitis / etiology
Vasculitis / immunology
Vasculitis / pathology

Substances

Antibodies, Monoclonal
Antigens, CD
Antigens, Differentiation
CD28 Antigens
CD40 Antigens
CTLA-4 Antigen
Ctla4 protein, mouse
Ctla4 protein, rat
Immunoconjugates
CD40 Ligand
Abatacept