Treatment with immunotoxin

T-cell depletion prior to or beginning at the time of transplantation has b een shown to be a valuable adjunct to the induction of immunological unresp onsiveness, Both total lymphoid irradiation and antilymphocyte globulin hav e been used for this purpose in experimental models of transplantation as well as in human organ transplant recipients. However, these methods of T-c ell depletion are limited in their ability to deplete T cells selectively d ue to non-specific targeting and limited efficacy. A new anti-CD3 immunotox in has been developed with a far more potent ability to deplete T cells sel ectively as measured by flow cytometry analysis of peripheral blood T lymph ocytes as well as lymph nodes lymphocytes. This immunotoxin is well tolerat ed by rhesus monkeys when administered in vivo. When administered as a sing le immunosuppressive agent pretransplant, it substantially promotes allogra ft survival, inducing tolerance in at least one-third of recipients as meas ured by subsequent acceptance of donor skin grafts and rejection of third-p art): skin grafts. When administered on the day of transplant in combinatio n with steroid pretreatment and a brief course of deoxyspergualin or mycoph enolate mofetil (4 to 14 days), long-term unresponsiveness is also produced and in a more reliable manner than using immunotoxin alone. A new immunoto xin directed at the human CD3 epsilon has been developed with excellent pot ency in T-cell killing and lacking the Fc portion of the CD3 antibody. This : construct ma) be useful for T-cell depletion in humans and has a potentia l application in tolerance induction in human organ transplantation. Lesson s learned from anti-CDS immunotoxin in the non-human primate model to date include (i) profound (2-3 log) depletion of T cells ran he accomplished saf ely without inducing lymphoma or infection, (ii) such depletion is a useful adjunct for tolerance induction to allogeneic organ transplants, and (iii) tolerance to both allogeneic renal transplants and xenogeneic islet transp lants has been accomplished using such strategies to date in non-human prim ates and in pigs. Immunotoxin ma): l,e useful for the induction of chimeris m using strategies that include donor bone marrow infusion. Successful stra tegies for tolerance induction hal e also been developed using immunotoxin without the adjunct of donor bone marrow or stem cell infusion. Clinical ap plication of immunotoxin will use a newly engineered construct with the pot ential for causing cytokine release, less susceptibility to neutralization by anti-diphtheria antibody and not dependent on chemical conjugation of an antibody and toxin. The usefulness of immunotoxin is directly related to i ts tremendous potency for depleting T cells. Based on results in nonhuman p rimates, it is anticipated that it will become a useful agent in tolerance induction in humans.