The major objective is the development of methods and reagents to modulate CD2 function to alter transplant immunity and prolong allograft survival. CD2 is important during the initial interaction of a T cell with antigen presenting membranes and serves three important roles at that time. First, CD2 functions as an adhesion molecule to strengthen intercellular interactions. Second, CD2 is a transmembrane signal transducer and provides messages to the cytoplasm. In some instances these are negative regulatory messages which impede activation. Third, CD2 associates with other surface receptors by sharing subunits, sharing second messenger pathways, or modifying the biochemical function of these receptors. The hypothesis is that by interfering with these roles of CD2, suboptimal antigen recognition will ensue. A reagent which modifies CD2 function may result not only in the failure to recognize antigen and immunologic silence, but also has the potential to induce tolerance and suppression. The first specific aim is to define methods to modulate CD2 function to prolong allograft survival.
Aim 1 A. Anti-CD2 mAbs will be used to prolong allograft survival in mice. Issues relating to epitope recognition, antibody isotype, dosing regimens, and mAb administered remote from transplantation require evaluation in order to expand and refine the use of anti-CD2 mAbs during allografting.
Aim 1 B. Soluble CD2 constructs (sCD2) produced in the baculovirus expression vector will be administered to prolong allograft survival. Comparisons of monovalent and polyvalent sCD2 and intact or fragmented anti-CD2 mAbs will help differentiate between adhesion and signaling functions of CD2 in vivo. The use of a novel agent such as CD2 will also provide information on the role of LFA-3 in immunity.
Aim 1 C. Anti-CD2 mAb or sCD2 will be combined with other mAbs to prolong allograft survival or achieve tolerance. Since CD2 interacts with other surface molecules, altering functions of both molecules may be more effective than modulating each molecule alone. The second specific aim is to define suppressor cells generated by anti-CD2 mAb. Anti-CD2 mAbs induce a negative regulatory subset of lymphocytes which require detailed phenotypic evaluation, assessment of the relative roles of antigen and mAb in their induction, and assessment of mechanism of suppression. The results may influence the immunosuppressive regimens examined in Aim 1A. The third specific aim is to define the determinants and consequences of down modulation of cell surface CD2. Anti-CD2 mAb induces down modulation of CD2 without affecting CD3, CD4, and CD8. The co-signals important for down modulation and the effects on other surface receptors are not currently known. The results will bear directly on the specificity of mAbs selected for Aim 1C and the immunosuppressive regimens examined in Aim 1A.
| Blazar, B R; Taylor, P A; Panoskaltsis-Mortari, A et al. (1998) A critical role for CD48 antigen in regulating alloengraftment and lymphohematopoietic recovery after bone marrow transplantation. Blood 92:4453-63 |
