ABSTRACT
We investigated the role of 4-1BB, a T cell co-stimulatory molecule, in alloimmune responses. In vivo mixed lymphocyte reactions showed that 4-1BB was preferentially expressed on actively dividing CD4(+) and CD8(+) T cells. Furthermore, following alloantigen challenge, the draining lymph nodes contained subpopulations of 4-1BB-expressing CD4(+) and CD8(+) T cells. 4-1BB-deficient C57BL/6 mice showed a delayed rejection of cardiac transplants mismatched for the major histocompatibility complex. Longer transplant survival was induced by blockade of 4-1BB/4-1BB ligand (4-1BBL) interactions using an anti-4-1BBL monoclonal antibody. Histological analysis showed that prolonged transplant survival in the 4-1BB-deficient and anti-4-1BBL-treated mice correlated with reduced lymphocytic infiltration and vasculitis in the donor heart tissue. Taken together, our data suggest that blockade of 4-1BB/4-1BBL interactions inhibited the expansion of alloreactive T cells and reduced CTL activity against host alloantigen, which in turn resulted in the prolongation of allograft survival. Blockade of the 4-1BB co-stimulatory pathway may be useful for preventing allograft rejection.
Subject(s)
Antibodies, Monoclonal/pharmacology , Graft Rejection/immunology , Graft Survival/immunology , Heart Transplantation/immunology , Receptors, Nerve Growth Factor/immunology , Receptors, Tumor Necrosis Factor/immunology , Tumor Necrosis Factor-alpha/metabolism , 4-1BB Ligand , Animals , Antigens, CD , Cell Division/immunology , Dendritic Cells/immunology , Female , Graft Rejection/prevention & control , Isoantigens/immunology , Isoantigens/metabolism , Lymphocyte Culture Test, Mixed , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Mutant Strains , Receptors, Nerve Growth Factor/antagonists & inhibitors , Receptors, Nerve Growth Factor/metabolism , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/metabolism , Signal Transduction/immunology , Skin Transplantation/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Transplantation, Homologous , Tumor Necrosis Factor Receptor Superfamily, Member 9Subject(s)
Coumarins/pharmacology , Hepatocytes/cytology , Hepatocytes/drug effects , Organ Preservation Solutions , Tissue Preservation/methods , Vitamin E/pharmacology , Adenosine , Alanine Transaminase/analysis , Allopurinol , Animals , Antihypertensive Agents/pharmacology , Cell Survival , Cold Temperature , Glutathione , Hepatocytes/physiology , Hypertonic Solutions , Insulin , Kinetics , Malondialdehyde/metabolism , Raffinose , Rats , Rats, Sprague-Dawley , Thiobarbituric Acid Reactive Substances/analysis , Time FactorsABSTRACT
Among the phagocytic leukocytes, monocytes have the important role of clearing out parasitic microorganisms. They accomplish this through production of toxic metabolites of oxygen. Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), a peptide that stimulates phosphoinositide (PI) hydrolysis in human leukocytes, including monocytes, binds to a unique cell surface receptor and stimulates superoxide generation, killing of Staphylococcus aureus, and activation of phospholipase D (PLD) in human monocytes. Preincubation of the cells with a PI-specific phospholipase C (PLC) inhibitor (U-73122), protein kinase C inhibitor (GF109203X), or intracellular Ca2+ chelator (BAPTA/AM) before the peptide stimulus totally inhibits the peptide-induced PLD activation and superoxide generation. On the other hand, tyrosine kinase inhibitor genistein only partially inhibits the peptide-induced processes. The peptide-induced bacteria killing activity shares regulatory mechanisms for PLD activation with the superoxide generation, which is inhibited in the presence of 1-butanol. We suggest that the peptide stimulates PLD downstream of PLC activation and PLD activation in turn is essential for the peptide-induced immunological functions such as the superoxide generation and killing of bacteria by human monocytes.
