Monitoring the immune function: a shot in the dark!!

Almost every transplant clinic I have, one of my patients will ask about reducing his or her immunosuppression. This happened again this week. Needless to say that this is one of the most frustrating area in transplantation where we lack reliable assays to assess immune function. It is like treating BP without having BP cuff waiting for syncope or stroke to adjust medications. We still rely on measuring IS drug levels, which impact individual’s immune systems differently, and we evaluate graft functions that are usually late markers for events. Numerous assays been suggested but none predict the immune function accurately.

I recently revisited this subject in the context of transplantation tolerance: These assays can be antigen specific, meant to evaluate donor-specific T-cell responses against recipient antigens measuring proliferation of donor T cells in mixed leukocyte reaction (MLR), measuring lysis of recipient T cells in cytotoxic T lymphocyte (CTL) assay, or measuring production of interleukins either with enzyme-linked immunosorbent (ELISA) assay or with enzyme-linked immunospot (ELISPOT) assay. Transvivo delayed-type hypersensitivity (DTH) assay uses an immune-deficient mouse as an “in vivo milieu” for the interaction between donor T-cells and the recipient antigens that are both injected in its footpads, causing swelling, relative to the level of sensitivity that can be quantified with a caliper. These assays may also be non-antigen specific by measuring regulatory cells like CD4⁺CD25^high T-cells known as Treg, plasmacytoid dendritic cells that were reported to promote a Th2-type response that is more tolerogenic.

I think that the most popular test that became FDA approved in 2008 is the ImmuKnow assay that I personally order for my patients in certain conditions. It measures the T-cell response to a non-specific polyclonal stimulus by quantifying the intracellular ATP production as a marker of the level of the cell immune function. A simple blood draw will give clinicians a level of ATP that classifies the patient into one of three categories: Low Immune cell response if the level is less than 225 ng/ml, Moderate between 226 and 524 and strong above 525. The problem is when you want to decide on an individual basis, a patient with level above 525 could still be overimmunosuppressed and acting among the numbers will be very misleading. Low numbers seem to correlate better with overimmunosuppression and in the case of low risk patients who’s level is below 100, we are more comfortable to reduce immunosuppression with close follow up. What I find useful is the variation from the individual baseline and in one study they found that variation of more than 50% correlated better with events. Although this test became very popular across the country, it is obviously not the answer we’re looking for as transplant nephrologists and extensive research is needed in this area. Cylex may be used as an additional marker along with other indicators of immune function like drug level, BK viremia, CRP, WBC.

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