A pilot study on the immunological effects of oral administration of donor major histocompatibility complex class II peptides in renal transplant recipients.

Oral tolerance is an important physiological mechanism of immune hyporesponsiveness to dietary antigens and the commensal flora of the gastrointestinal tract. Feeding of alloantigens, therefore, has the potential to suppress undesirable immune responses after transplantation. To date, there are no published reports on the effects of such an approach in human transplant recipients. In the present pilot study, we demonstrate complete suppression of baseline indirect alloreactivity in patients with chronic renal allograft dysfunction following the oral feeding of low (0.5 mg/d) but not higher (1.0 and 5.0 mg/d) doses of donor major histocompatibility complex (MHC) class II peptides. The regimen was well tolerated with no evidence for sensitization to the donor antigen. Our results indicate that oral feeding of low dose donor MHC peptide may represent a safe and effective therapy to suppress indirect alloreactivity in renal transplant recipients with chronic allograft dysfunction and warrants further clinical investigation.

Human T and natural killer cells possess a functional renin-angiotensin system: further mechanisms of angiotensin II-induced inflammation.

The renin-angiotensin system (RAS) plays an important role in the regulation of inflammation and in the progression of chronic kidney disease. Accumulation of inflammatory cells into the renal parenchyma has been a hallmark of chronic kidney disease; however, little is known concerning the presence and the function of RAS elements in T and natural killer (NK) cells. Here is reported a co-stimulatory effect of angiotensin II (AngII) by showing an augmentation of mitogen and anti-CD3-stimulated T and NK cell proliferation with AngII treatment. Angiotensinogen and AngI also generated the same effect, suggesting that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they express renin, the renin receptor, angiotensinogen, and angiotensin-converting enzyme by mRNA analysis. Flow cytometric analysis and Western blot revealed angiotensin receptor 2 (AT(2)) expression in T and NK cells, whereas AT(1) expression was found in T and NK cells and monocytes by Western blot. These receptors were shown to be functional in calcium signaling, chemotaxis, and proliferation. However, AT(1) and AT(2) antagonists alone or in combination were unable to abrogate completely the effects of AngII, suggesting that another AngII receptor may also be functional in leukocytes. This is the first study to show that T and NK cells are fully equipped with RAS elements and are potentially capable of producing and delivering AngII to sites of inflammation. Because their chemotaxis is enhanced by AngII, this creates a potential inflammatory amplification system.

Avoidance of cyclosporine in renal transplantation: effects of daclizumab, mycophenolate mofetil, and steroids.

Cyclosporine (CsA) has been implicated in both acute and chronic graft dysfunction. The addition of humanized IL-2 receptor antibody daclizumab (DZB) to CsA-based immunosuppression decreases the rate of acute renal transplant rejection. Therefore, 45 patients were evaluated in an immunosuppressive protocol that included DZB, mycophenolate mofetil (MMF), and steroids without CsA. This was a prospective, nonrandomized, open-label trial of the efficacy and safety of the treatment. DZB was given intravenously at 2 mg/kg before transplantation and then at 1 mg/kg every 2 wk for four doses, MMF was given orally at 3 g/d, and methylprednisolone/prednisone was given at 7 mg/kg per day and tapered to 15 mg/d at 6 mo. CsA was added to the regimen when patients developed acute rejection episodes or adverse effects to steroids or MMF; 49% of patients were spared CsA maintenance. Patients without CsA had lower serum creatinine at 6 mo and needed fewer medications to control BP. Incidence of biopsyproven rejections was 31% and occurred early (median, 10 d). These rejection episodes occurred earlier in cadaver transplants (median, 7 d) and later in living donor transplants (median, 62 days). Acute rejections occurred at a higher frequency (46% versus 34%) and earlier (6.5 versus 15 d) in patients with delayed graft function compared with patients without delayed graft function. Most of the rejections were moderate and easily reversible. The actuarial 1-yr graft survival was 95% with 100% patient survival.

Effect of anti-IL-2Ralpha antibody on IL-2-induced Jak/STAT signaling.

Acute allograft rejection is driven by production of cytokines such as interleukin-2 (IL-2) that activate and expand alloreactive T cells by ligating high-affinity IL-2 receptors composed of three subunit chains: alpha, beta, gamma The alpha chain, expressed only on activated T cells, has become an important therapeutic target. Monoclonal antibodies (mAbs) that bind IL-2Ralpha chains significantly decrease transplant rejection. We examined the ability of the humanized anti-IL-2Ralpha antibody daclizumab to block high-affinity IL-2Rs and interrupt T-lymphocyte signaling. Our evaluation focused on a pathway critical for T-cell proliferation, the Jak/STAT pathway. Daclizumab markedly inhibited phosphorylation of the Jak1, Jak3 and STAT5a/b components of the IL-2R-dependent pathway. Suppression by daclizumab was associated with internalization of IL-2Ralpha but not IL-2Rbetagamma chains. High IL-2 doses overcame daclizumab-induced blockade of Jak/STAT phosphorylation despite absent cell surface highaffinity IL-2Rs. Under these circumstances, IL-2-mediated Jak/STAT pathway activation might be generated through residual intermediate affinity IL-2Rbetagamma receptors, and this was demonstrated by complete blockade of signaling when anti-IL-2Rbeta monoclonal antibody was added. Humanized antibodies are an important part of strategies to induce alloantigen tolerance. Understanding the molecular events associated with their beneficial clinical effect is critical to design of future immunosuppressive strategies.