An anti-CD103 immunotoxin promotes long-term survival of pancreatic islet allografts.

Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103+ cells from wild type hosts. To circumvent this problem, we conjugated the nondepleting anti-CD103 monoclonal antibody, M290, to the toxin, saporin, to produce an immunotoxin (M290-SAP) that efficiently depletes CD103+ cells in vivo. Herein, we show that M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in the blood, spleen, mesenteric lymph nodes and intestinal epithelium of treated mice. We further demonstrate that M290-SAP promotes indefinite islet allograft survival in a fully MHC mismatched mouse model. The prolonged islet allograft survival resulting from M290-SAP treatment was associated with multiple effects in the host immune system including not only depletion of CD103-expressing leukocytes, but also an increase in CD4+CD25+FoxP3+ T regulatory cells and a predominance of effector-memory CD8 T cells. Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in allograft rejection.

Long-term performance of prostheses in mitral valve replacement.

The long-term performance of prostheses in mitral valve replacement (MVR) is now available with representatives of current generation prostheses to 15 years. Mechanical prostheses have been implanted for 33 years and bioprostheses for 22 years. The predominant complication of mechanical prostheses is hemorrhage from anticoagulation and reoperation for late structural valve deterioration of bioprostheses. Mitral valve (MV) reconstruction, over MVR, is recommended whenever possible, especially with the advancement of atrial fibrillation ablation techniques. The current indications for MVR are those valvular lesions that are unlikely to be repaired by most surgeons or which long-term results are suboptimal with reconstruction. Reconstruction is more common for degenerative disease, replacement for rheumatic disease and variable for advanced ischemic and infective disease. The recommendations for MVR for mitral stenosis (MS) are moderate to severe MS with advanced functional status and severe pulmonary hypertension when percutaneous balloon valvotomy or mitral reconstruction is not feasible. MVR is recommended in non-ischemic severe mitral regurgitation (MR) and for non-reparable acute symptomatic MR, advanced symptomatic status, systolic dysfunction and/or ventricular dysfunction. The recommendations for MV surgery in ischemic MR are acute post-infarction MR with cardiogenic shock, unstable angina with persistent moderate-severe and severe MR and chronic, dilated ischemic cardiomyopathy with moderate-severe and severe MR.

An ex vivo model of tolerance vs. rejection: comparison of different signal transducers and activators of transcription, STAT1, STAT4, STAT5 and STAT6.

An ideal for clinical organ transplantation is for the recipient to develop graft-specific immune tolerance. Although tolerance may occur, there is no way of identifying those recipients who are tolerant vs. those still capable of rejecting their graft. Thus immunosuppressive therapy is normally continued throughout life with the attendant risks of infection, neoplasia, and unwanted side effects of the immunosuppressive drugs. A surrogate marker of specific immune non-responsiveness would permit identification of graft-tolerant individuals who may then be weaned off all immunosuppression. Here we present a model which characterises discrete components of a tolerant, vs. aggressive, immune response. In rodents, new populations of tolerant, regulatory cells can be generated for a foreign graft if first exposure of the T cell receptor (TCR) to graft antigen coincides with blockade of the CD4 and CD8 co-receptors of the TCR. Once established, this type of peripheral tolerance is very robust. We have exploited an ex vivo model to compare in vivo-derived allo-tolerant lymphocytes with their counterpart which have been primed to reject the same allo-antigen. The model has revealed differential STAT (Signal Transducers and Activators of Transcription) responses associated with tolerance, vs. rejection, which have not been previously described. This approach will identify candidate surrogate markers of immune response status for potential clinical application.