Impact of maintenance immunosuppressive regimens - balance between graft protective suppression of immune functions and a near physiological immune response

Abstract

Summary The Symphony study showed superior 1‐year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin‐secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post‐transplant. Tacr‐ compared with CsA‐based immunosuppression was independently associated with increased IL‐2 (P < 0.0001, CD4 cells; P = 0.014, CD8 cells) and CD4 cell IL‐4 responses (P = 0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL‐10 responses (P = 0.008), B‐cell IL‐6R expression (P < 0.0001) and ISC formation [P = 0.020, staphylococcus cowan strain I (SAC I); P = 0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL‐4 by Tacr, decreased CD4 cell IL‐10 responses by MMF) and suppression of B‐cell functions (MMF), whereas Tacr/Aza was associated with physiological IL‐2 and IL‐4 and stronger humoral responses which may reduce the risk of infectious disease complications. (ClinicalTrials.gov number: NCT00150891).

Factors Affecting Graft Survival among Patients Receiving Kidneys from Live Donors: A Single-Center Experience

“…In their study, a combination of tacrolimus/azathioprine (Tac/Aza) provided a better result than that of tacrolimus/mycophenolate mofetil (Tac/MMF). A possible explanation is that while Tac/MMF can provide a more potent immunosuppression, Tac/Aza is associated with a reduced risk of infectious complications [18]. …”

Comparative pharmacokinetic study of two mycophenolate mofetil formulations in stable kidney transplant recipients

“…Alternatively, subjects could undergo a shortened 6‐h PK profile. For calculation of the full PK profile from the 6‐h data, a previously published algorithm [6] was used and validated for our population (data not shown).…”

“…To fill this void, we performed an international, multi‐centre crossover study comparing steady‐state PKs and adverse events of CellCept ® (Roche) and Myfenax ® in kidney transplant recipients. The use of MMF together with tacrolimus has been clinical practice in transplant care for several years [4,5], and has also the most effective impact on graft protective Th2 responses in vitro [6]. Currently, this combination is not an approved indication in the European Union (EU) for both formulations, Myfenax ® and CellCept ® .…”

Safety profile comparing azathioprine and mycophenolate in kidney transplant recipients receiving tacrolimus and corticosteroids

“…A relevant increase of 28% was seen in CMV infection, with a 4‐fold increase in the incidence of PVN in patients receiving MPA vs. AZA. Experimental studies suggest that MPA use is associated with a depressed antibody‐mediated immunologic response, as indicated by measurement of lower interleukin‐10 lymphocyte production, lower CD4‐receptor expression, and lower immunoglobulin secretion . However, MPA use was not an independent risk factor for development of any infection or CMV infection in the multivariable analysis in the ITT population.…”