Anti-CD2 receptor and anti-CD2 ligand (CD48) antibodies synergize to prolong allograft survival.

Abstract

SummaryIndefinite graft survival was obtained with murine cardiac allografts using the combined administration of monoclonal antibodies (mAbs) directed against the receptor ligand pair CD2-CD48. Although each antibody could prolong graft survival when given alone, neither resulted in the indefinite graft survival seen with the combination. Combined mAb administration is associated with inhibition of T cell priming and help and subsequent cytotoxic T lymphocyte generation. This indicates that the interaction between CD2 and its ligand is important for antigen priming and recognition, and combined mAbs may prove to be a useful therapeutic regimen for transplantation.T olerance induction is the major goal in transplantation.It has been obtained with several regimens including the administration of pairs of mAbs to CD4 and CD8 (1), CD2 and CD3 (2), and CDlla/CD18 and CD54 (3). The combined use of antireceptor plus antiligand mAbs may be advantageous in blocking both T cells and APCs, and in blocking interactions with as yet unknown ligands. Recent findings have identified murine CD48 (4), and human CD59 (5, 6), and sulfated carbohydrates (7) as potential ligands for CD2, in addition to the well-characterized human ligand CD58 (LFA-3). Murine CD48 (Blast-I, BCM1) has structural homology to human CD58, including glycosyl-phosphatidylinositol linkage to the cell membrane, and functions in signal transduction and activation of lymphoid cells (4,(8)(9)(10). CD2 is important in adhesion and signal transduction (11,12), and anti-CD2 mAbs suppress cell-mediated immunity (13,14) and prolong allograft and xenograft survival (15). With the recent availability of mAbs defining this receptor-ligand pair, the combination of anti-CD2 plus anti-CD48 mAbs was administered in a murine cardiac allograft model and indefinite graft survival was observed. The induction of indefinite graft survival is associated with inhibition of T cell priming and help and subsequent CTL generation, while maintenance of tolerance is associated with a lack of T cell help. This indicates that CD2-CD48 interactions and signals are integral to antigen priming and recognition, and combined mAbs are an important therapeutic regimen for transplantation. Materials and MethodsAnimals. CBA/J (H-2 k) and BALB/cByJ (H-2 d) female mice, 8-10-wk-old, were purchased from The Jackson Laboratory (Bar Harbor, ME). Timed pregnant C57BL/6 (H-2 b) and BALB/c mice were purchased from Harlan Sprague Dawley, Inc. (Indianapolis, IN) and were used as the donor strains.Reagents. The 12-15 rat IgG1 anti-routine CD2 hybridoma (16), a gift of Dr. Peter Ahevogt (Immunology and Genetics Institute, Heidelberg, Germany), and the HM48-1 hamster IgG anti-murine CD48 (4) were grown in culture and purified over protein G (Pharmacia, Piscataway, NJ). For control mAbs the YTS-259 rat IgG1 anti-ras (17) was used. Abs were injected intravenously in PBS or were used in vitro at specified concentrations.Cardiac Transplantation. Donor embryonic (E 18-21) or neonatal (P 1-2) C57BL/6 or BALB/c mice ...

Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion

“…Various immunosuppressive molecules have been tested in a variety of transplantation models and need to be assessed for their effectiveness on graft prolongation. In one of the strategies examined, the blockade of co-stimulatory signals by immunosuppressive proteins has been shown to prolong allograft survival in various transplantation settings [10,11]. In T cell-mediated immunity, the full activation of naïve T cells requires co-stimulatory signals generated by the ligation of CD28 on T cells with their receptor, B7-1/B7-2, on antigen-presenting cells (APCs) [12].…”

The counterreceptor binding site of human CD2 exhibits an extended surface patch with multiple conformations fluctuating with millisecond to microsecond motions

“…the average of the spectral density function at the proton frequency as well as the sum and difference of the proton and nitrogen frequencies; T , , overall tumbling time; GlcNAc-I , N-acetylglucosamine. vation signals that synergize with those mediated by the TCR (Meuer et al, 1984;Bierer et al, 1988), and in vivo studies in rodents have shown that administration of anti-CD2 monoclonal antibodies effectively prolong allograft survival (Chavin et al, 1993;Qin et al, 1994). Moreover, the CD2-CD58 pathway plays a critical role in the maintenance and reversal of anergy (BoussiOtis et al, 1994), and anti-CD2 and anti-CD58 mAbs can specifically inhibit interleukin-12-induced proliferation and interferon y production by activated T cells (Gollob et al, 1995).…”

A novel role for CD28 in thymic selection: elimination of CD28/B7 interactions increases positive selection

“…The cytoplasmic domain of CD5 has an immunoreceptor tyrosine-based inhibition motif (ITIM) and has been shown to negatively regulate signaling through both the TCR and BCR [27,29]. In vitro and in vivo studies with anti-CD2 antibodies revealed inhibition of T cell function, including longlasting hyporesponsiveness, that could not be entirely explained simply by blockade of CD2 interactions with its ligand [30,31]. Thus, both CD2 and CD5 appear capable of antagonizing T cell activation, whereas in contrast, CD28 has only been reported to augment mature T cell activation.…”