Tolerogenic immunosuppression for organ transplantation

Abstract

Background: Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants.

Methods: 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals.

Findings: We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13-18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11).

Interpretation: The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

Figure 1. Course of treatment of a cadaveric-kidney recipient

Biopsy-proved rejection (Banff 1A) in the third week was treated with boluses of 1·0 g and 0·5 g prednisone. Similar findings in later biopsy specimens were not associated with renal function changes and were not treated. Instead, weaning was begun at 7 months. At 16·5 months, treatment was one dose per week tacrolimus.

Figure 2. Biopsy specimen of cadaveric-kidney transplant

(Left) Needle biopsy sample of the allograft in figure 1 at 4 months; haematoxylin and eosin staining ×40. (Right) Banff grade 1A (mild) rejection; haematoxylin and eosin staining ×200. Repeat biopsy specimens taken in subsequent months were closely similar.

Figure 3. Course of treatment of a cadaveric-kidney recipient with pre-existing nephropathy

Five biopsy specimens taken over a period of 10 months had Banff rejection grades of either borderline or 1, prompting steroid boluses. Tacrolimus doses were first reduced from daily to two times per week (months 6·5–10), then temporarily restored to daily, and eventually established at three times per week.

Figure 4. Four categories of treatment in the first 12 months for 47 kidney recipients whose grafts still function after 13–17 months

Numbers represent category of treatment. 81–90% of patients in any given month were on tacrolimus monotherapy (category 1) or nearly so (category 2 and 3).

Figure 5. Protocol violation in recipient of a cadaver kidney that sustained a severe ischemia-reperfusion injury

Daily sirolimus (doses stacked on tacrolimus doses) and prednisone boluses plus daily steroid treatment were added to tacrolimus in the third week because of biopsy findings of mild (Banff 1A) rejection. A return to tacrolimus monotherapy after 7 months was succeeded by a Banff 2A (moderate) rejection and restoration of multiple drug immunosuppression.

Figure 6. Banff grades of allograft biopsy specimens obtained in 50 kidney recipients

Solid circles represent recipients in whom biopsy sample was taken. Small open circles depict patients with no biopsy sample and no clinical evidence of rejection. Large open circles depict biopsy procedures of kidneys lost at 90 (F1) and 240 (F2) days. ACR=acute cellular rejection.

Figure 7. Four categories of treatment in the first 12 months for 14 liver recipients who survive after 13–17 months

Note that the proportion of people who needed category 3 and 4 immunosuppression during the first 60 days was comparable with that in the kidney recipients (figure 4).

Figure 8. Mechanisms of immunosuppression

(Left) Conversion of rejection (thick dashed arrow) to an immune response that can be exhausted and deleted by combination of pretreatment and minimalistic post-transplant immunosuppression. (Right) If the clonal response is eliminated by excessive post-transplant immunosuppression, exhaustion-deletion shown on the left is precluded, and subsequent graft survival is permanently dependent on immunosuppression. GVH=graft-versus-host; HVG=host-versus-graft; Tx=transplantation.