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Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ng/mL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum and/or C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.

Campath-1H (Alemtuzumab) is an effective immunodepletion agent used in renal transplantation. To evaluate its influence on T lymphocytes during repletion, we analyzed peripheral blood from Campath-1H-treated renal allograft recipients for the presence of FOXP3(+) regulatory T (Treg) cells. Flow cytometry demonstrated that CD4(+)CD25(+)FOXP3(+) lymphocytes increased significantly within the CD4(+) T-cell population, skewing Treg/Teff (T effector) ratios for up to several years. In contrast, Treg levels in patients treated with anti-CD25 (Basiliximab) and maintained on CsA demonstrated a sustained decrease. The increase in Tregs in Campath-1H treated patients developed independent of maintenance immunosuppression. Importantly, the increase in Tregs was not fully explained by their homeostatic proliferation, increased thymic output, or Treg sparing, suggesting de novo generation/expansion. Consistent with this, in vitro stimulation of PBMCs with Campath-1H, with or without anti-CD3, activation led to an increase in CD4(+)CD25(+)FOXP3(+) cells that had suppressive capabilities. Together, these data suggest that Campath-1H promotes an increase in peripheral Tregs and may act as an intrinsic generator of Tregs in vivo.

Background: Kidney transplant patients given Campath-1H (Alemtuzumab) immunodepletion therapy and long-term rapamycin monotherapy have excellent graft survival and function at three years. As an initial step in understanding the characteristics of repopulated T lymphocytes in these patients, we performed several assays to assess alloreactivity., Methods: We measured T-cell responses using CFSE-labeled recipient lymphocytes in a direct one-way MLR, and also analyzed the kinetics of expression of IFN-gamma. We examined the T-cell responses of Campath-treated transplant patients on monotherapy versus those treated with anti-CD25 (Basiliximab) induction therapy and maintenance immunosuppression consisting of cyclosporine A, mycophenolate mofetil, and steroids., Results: On average, proliferative responses to donor antigen were equal between Campath and control groups. However, the Campath group displayed a greater response to third party compared to donor antigen (CD3 P = 0.04, CD4 P = 0.07, CD8 P < 0.01), whereas the control group did not display a greater response to third party (CD3 P = 0.69, CD4 P = 0.72, CD8 P = 0.60). Interestingly, more Campath patients (4 of 15) than control patients (0 of 8) displayed donor specific unresponsiveness as gauged by IFN-gamma expression and T-cell proliferation (P = 0.15)., Conclusions: These studies suggest that Campath-1H in conjunction with rapamycin monotherapy retains intact immune responses to third party alloantigen, yet may promote hyporesponsiveness to donor antigen.

Background: In this study, we determined whether Campath-1H induction followed by sirolimus monotherapy inhibited alloantibody production in renal transplantation. Second, we evaluated the correlation between human leukocyte antigen (HLA) antibody production and serum creatinine levels., Methods: Sera were taken 1 to 24 months after transplantation from 24 patients treated with Campath-1H and sirolimus and tested for serum creatinine and HLA-specific antibody by using flow cytometry and enzyme-linked immunosorbent assay., Results: Ten (42%) of the 24 patients treated with Campath-1H and sirolimus produced HLA antibodies. Six of these 10 developed both donor-specific antibodies (DSAs) and non-donor-specific antibodies (NDSAs), whereas only NDSAs were detected in the other four patients. In patients with biopsy-diagnosed humoral rejection (C4d+), serum levels of both DSA and NDSA significantly correlated with patient serum creatinine levels. Rejection treatment successfully reduced both DSAs and NDSAs and reversed humoral rejection., Conclusions: The numeric relationship between serum creatinine and DSA levels suggests a causal relationship between alloantibody and transplant rejection.

Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.