In our retrospective analysis of GVHD after liver transplantation, we found that the use of anti-IL-2 alpha chain receptor antibody as induction for liver transplantation seemed to be temporally related to a spike in the incidence of GVHD after liver transplantation, with an incidence over 1.5%. Since switching to thymoglobulin, we have not seen any further cases of GVHD in the past 300 cases. For those of you that respond, can you state how many cases of GVHD you have seen, mortality rate and association with the use of basiliximab.
To be honest John we have seen very few GvHD but the last one I remember had Il-2 induction. I have seen in MvTx with ATG as well
michael
Thanks Michael, in the beginning of 2013, we saw 5 cases in our first 60 patients in the first 5 months. All were severe, we actually lost one patient, even with our protocol for Alefacept treatment. This was so high that had to do some change to immunosuppression. Our low risk patients get only tacrolimus and steroids, the high risk patients including patients with renal failure, get thymo with delayed tacrolimus. In the past 200 patients since then, we have not seen any cases.
We have seen GvHD only in the context of MvTX and ITX with basiliximab. In > 200 isolated LTX in pediatric patients from 2 centers on basiliximab induction and consecutive tacrolimus immunosuppression I have not seen a single case with GvHD.
Ekkehard
We have used Basiliximab for induction in LTX (>800 patients) since the late nineties (phase II and III trials and later as compassionate use). During this time only one GvHD case was observed and published (Transplantation, 73(2), 27 January 2002, pp 307-310). Since basiliximab is very selective blocking the IL-2 pathway, has no side effects, offers the opportunity of low baseline immunosuppression and particularly a low opportunistic infection rate, the question is rather how this profile compares to e.g. thymoglobulin or alemtuzumab as induction therapy. In our case the patient was successfully treated with close monitored discontinuation of immunosuppression and GvHD resolved. We assumed the liver as origin of the GvHD and the rather mild immunosuppression as confounding reason. Hence low or selective initial immunosuppression (block IL-2 receptors vs. T-cell elimination), rather seems to be the case. Low initial immunosuppression on the other hand works well in the setting of our transplant population, since the risk for GvHD seems to be obviously lower than in Cleveland.
Well, regarding ATG induction, it is a matter of definition. In a tolerance protocol with high bolus doses it would theoretically be a higher incidence, but we have seen very few cases. I will certainly look back on our IL-2 induction patients again
My question relates to the impact of basiliximab on Tregs, which are CD25+. There is evidence that basiliximab can deplete Tregs, is anti-tolerogenic, enhances anti-tumor responses. As Tregs are involved in GVHD by suppressing alloreactive T cells, there is a theoretical connection between the two events.
Well, basiliximab is coating the alpha chain of the IL-2 R, so far, there was and is no evidence that we are dealing with a depleting antibody (Amlot PL, Rawlings E, Fernando ON, Griffin PJ, Heinrich G, Schreier M, et al. Prolonged action of a chimeric interleukin-2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation. Transplantation 1995; 60:748).
The Analysis of the immunodynamics of basiliximab did not indicate depletion as well (attached manuscript). So far, there is no clinical evidence that baxiliximab is anti-tolerogenic. If you look into the "Combo Trial" where we used Daclizumab, MMF and steroids for baseline immunosuppression without CNI, the AR rate was 53% and just delayed to start after IL-2 mAb levels were gone (Transplantation. 2001 May 15;71(9):1282-7). The immune system is quite unimpressed by a short use of IL-2 mAb
These observations are interesting given that basiliximab was actually associated with a lower incidence of acute GVHD (compared with a group with no anti-CD 25 mAb) in an early bone marrow transplant study from 2005 at: http://www.nature.com/bmt/journal/v36/n4/full/1705046a.html
Also basiliximab appears to be quite effective therapy for refractory severe acute GVHD in bone marrow transplant recipients. See report at:
http://www.nature.com/bmt/journal/v37/n10/full/1705306a.html
Possibly the differences in baseline immunosuppression protocol agents (and dosages) between the liver transplant recipients and the bone marrow transplants could modulate the impact of basiliximab on the propensity for acute GVHD?
In line with very old data by Medawar on tolerogenic signals, I believe that any deleting T-cell agent given after transplantation or given as a too long course, will effect the T-regs negatively. The T-regs in ATG use will appear only if you give a high dose before or at the time of transplantation. Prolonged treatment after transplantation will kill also the T-regs, that have enough "room" to act after a depleting agent. In other words, the action of basiliximab will certainly depend on the baseline immunosuppressive protocol.
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