The major goal in organ transplantation is to prevent rejection yet preserve the immunocompetence of the recipient.Nonspecific immunosuppressive agents are currently the only method available to prevent rejection.Because of their mechanism of action,an increased rate of infection and malignancy accompanies their use.To overcome these limitations, attempts have been made to induce donor specific transplantation tolerance with preservation of immunocompetence.Although fully allogeneic chimeras (A=>B) are tolerant, they exhibit failure of engraftment,poor immunocompetence,and are prone to graft versus host (GVH) disease.We have developed a model for MIXED ALLOGENEIC RECONSTITUTION in which T-cell depleted (TCD) syngeneic plus TCD allogeneic bone marrow are transplanted into an lethally irradited recipient.Engraftment is reliable, tolerance induction occurs in 100% of recipients, the immunocompetence of the mixed chimeras is superior,and recipient animals are resistant to GVH disease.We have observed that both host and donor factors play a role in the balance of engraftment of allogeneic bone marrow stem cells.The model we have developed will be exploited to identify and subsequently isolate THE CRITICAL CELL(S) OF BOTH HOST AND DONOR TYPE WHICH FACILITATE ENGRAFTMENT OF ALLOGENEIC BONE MARROW STEM CELLS.There is data to suggest that T-cells are essential for stem cell engraftment.Initially,we will focus on those allogeneic donor bone marrow cell(s) which facilitate engraftment of allogeneic stem cells [FACILITATORY CELL].Once the FACILITATORY CELL is identified,we propose to ISOLATE IT AND CO-ADMINISTER IT WITH PURIFIED STEM CELLS PLUS T-CELL DEPLETED SYNGENEIC BONE MARROW TO ACHIEVE MIXED CHIMERISM AND TOLERANCE (Specific Aim 2).We will characterize the production of INTERLEUKINS and COLONY STIMULATING FACTORS in an attempt to determine whether these soluble factors can SUBSTITUTE FOR THE FACILITATORY CELL in facilitation of allogeneic stem cell engraftment.We will then focus on the SYNGENEIC host cells which,when present,PREVENT ENGRAFTMENT of allogeneic donor bone marrow stem cells (Specific Aim 3),AND APPLY THE KNOWLEDGE obtained to preparation of ANTIBODY-FACILITATED MIXED CHIMERAS.What we are seeking is a method to allow the induction of MIXED ALLOGENEIC CHIMERISM,WITH ITS ACCOMPANYING ADVANTAGES OF SUPERIOR IMMUNOCOMPETENCE AND RESISTANCE TO GVH DISEASE IN ADDITION TO SPECIFIC TOLERANCE, USING ONLY MONOCLONAL ANTIBODY CONDITIONING.In effect, a focused, component approach will be applied to engraftment and tolerance induction.
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