ABSTRACT
OBJECTIVE: To determine the immunomodulatory effects of the anti-rat CD28 monoclonal antibody (Mab) JJ316 on the onset of rat adjuvant arthritis (AA). JJ316 is a superagonistic Mab that induces polyclonal T cell proliferation in the absence of T cell receptor (TCR) ligation and promotes the expansion of regulatory T cells. METHODS: Female Wistar rats in which AA was induced were treated with JJ316 on Day 0 and Day 9 postinduction. A parallel treatment with JJ319, a "conventional" CD28-specific Mab that costimulates anti-TCR triggered proliferation, was performed. Severity of arthritis was monitored by means of an arthritic score, and by recording hindpaw volume and body weight increases. Serum antibodies against the AA-inducing mycobacteria were also determined by ELISA. To ascertain the effect of JJ316 on T lymphocytes in vivo, blood CD4+CD45RChigh (Th1-like) and CD4+CD45RClow (Th2-like) cells were analyzed by flow cytometry, and the relative levels of interleukin 2 (IL-2), IL-10, and interferon-g (IFN-g) mRNA in synovial tissue were measured by real-time reverse transcription-polymerase chain reaction. RESULTS: JJ316 efficiently prevented the inflammatory process of AA. This effect was associated with a specific decrease in the blood CD4+CD45RChigh/CD4+CD45RClow T cell ratio and high IL-10 mRNA expression in the synovia. In addition, anti-mycobacteria antibody levels decreased in JJ316 treated animals. In contrast, administration of the conventional anti-CD28 Mab JJ319 did not improve inflammation. CONCLUSION: JJ316, a stimulatory CD28-specific Mab known to promote Th2 function and the expansion of regulatory T cells, provides effective protection from AA.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Arthritis, Experimental/therapy , CD28 Antigens/immunology , Immunologic Factors/therapeutic use , Animals , Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Cell Count , Cytokines/genetics , Cytokines/metabolism , Female , Hindlimb/drug effects , Hindlimb/pathology , Mycobacterium/immunology , RNA, Messenger/analysis , Rats , Rats, Wistar , Synovial Membrane/drug effects , Synovial Membrane/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathologyABSTRACT
Two distinct CD28-specific mAb were used in treatment of active or adoptive transfer (AT)-experimental autoimmune neuritis (EAN): "superagonistic" JJ316 activates T cells without T cell receptor (TCR) occupancy, and conventional JJ319 activates T cells only in the presence of TCR-stimulation. Treatment with JJ316 during induction phase of active and adoptive-transfer experimental autoimmune encephalomyelitis (AT-EAN) dramatically reduced disease severity and improved nerve function as revealed by electrophysiology. JJ316 given 1 week before immunization had a preventive effect. By immunohistology, JJ316 markedly reduced TC infiltration of the sciatic nerve in active and AT-EAN. JJ319 was less effective. Ex vivo, JJ316 therapy reduced P2-specific proliferation and interferon-gamma (IFN-gamma) production of lymph node cells. We demonstrate preventive and therapeutic effects of a "superagonistic" mAb-mediated, TCR-independent CD28 stimulation in EAN, possibly with implications for therapy of autoimmune-inflammatory disorders.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , CD28 Antigens/immunology , Epitopes, T-Lymphocyte/immunology , Neuritis, Autoimmune, Experimental/immunology , Neuritis, Autoimmune, Experimental/prevention & control , Adoptive Transfer , Animals , Cell Division/immunology , Cell Line , Cell Movement/immunology , Cells, Cultured , Female , Immunity, Active , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Injections, Intraperitoneal , Interferon-gamma/biosynthesis , Lymphocyte Activation/immunology , Myelin P2 Protein/immunology , Neuritis, Autoimmune, Experimental/pathology , Neuritis, Autoimmune, Experimental/physiopathology , Peptide Fragments/immunology , Rats , Rats, Inbred Lew , Sciatic Nerve/immunology , Sciatic Nerve/physiopathology , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , T-Lymphocytes/transplantationABSTRACT
Slow recovery of T-cell numbers and function contributes to the high incidence of life-threatening infections after cytotoxic cancer therapies. We have tested the therapeutic potential of a novel class of superagonistic CD28-specific antibodies that induce polyclonal T-cell proliferation without T-cell receptor engagement in an experimental rat model of T lymphopenia. We show that in lethally irradiated, bone marrow-reconstituted hosts, CD28 superagonist is able to dramatically accelerate repopulation by a small inoculum of mature, allotype-marked T cells. CD28-driven recovery of CD4 cells was superior to that of CD8 T cells. CD28 superagonist- expanded CD4 T cells had maintained repertoire diversity and were functional both in vitro and in vivo, suggesting that treatment with a human CD28-specific superagonist will protect T-lymphopenic patients from opportunistic infections.