Expansion of NKG2A-LIR1- natural killer cells in HLA-matched, killer cell immunoglobulin-like receptors/HLA-ligand mismatched patients following hematopoietic cell transplantation.

The prognosis after hematopoietic cell transplantation (HCT) for the treatment of leukemia or lymphoma in humans is influenced by donor-derived natural killer (NK) cells, which enhance the graft-versus-leukemia (GVL) effect. Such alloreactive killer cells can be generated in vivo after HCT if the donor expresses killer cell immunoglobulin-like receptors (KIRs), such as KIR2DL1, KIR2DL2/3, or KIR3DL1, for which the recipient lacks HLA class I ligands. We studied effector cells from 22 KIR/HLA-ligand mismatched and 14 KIR/HLA-ligand matched, primarily HLA-matched patient-donor pairs after allogeneic HCT. A novel 8-color flow cytometry panel allowed us to characterize effector-cell populations without "broadly reactive" inhibitory receptors such as CD94/NKG2A or LIR1. The numbers of such NKG2A(-) LIR1(-) NK cells increased following HCT in patients transplanted by KIR/HLA-ligand mismatched grafts, compared to KIR/HLA-ligand matched grafts, and in patients transplanted from donors of the A/B, compared to A/A, KIR haplotypes. NKG2A(-)LIR1(-) NK cells expressing only those inhibitory KIRs for which the patient had no HLA class I ligands could be stimulated by HLA class I-deficient cells to express CD107a. Thus, NKG2A(-)LIR1(-) NK cells may be important GVL effector cells following HCT, even in patients transplanted from HLA-matched donors.

Preemptive postoperative antigen-specific immunoadsorption in ABO-incompatible kidney transplantation: necessary or not?

Several standard protocols for ABO-incompatible kidney transplantation use scheduled preemptive antigen-specific immunoadsorption during the postoperative period. Our center has developed a different approach. Our patients undergo antigen-specific immunoadsorption postoperatively only if their isoagglutinine titers (immunoglobulin G anti-A/B) exceed 1:8 in the first postoperative week and 1:16 in the second postoperative week. Using this strategy, 22 ABO-incompatible kidney transplantations have been performed at our center since 2004. Only 32% of these patients (7 of 22) needed to undergo postoperative immunoadsorption (mean 4.1 immunoadsorption sessions per patient). The renal outcome in patients receiving postoperative immunoadsorption treatment versus the outcome in patients without postoperative immunoadsorption remained equal at a mean follow-up of 17 months. We identified a shorter pretransplant time on dialysis, a blood type constellation of donor A1/recipient O, and high initial starting titers as predictors for the need for postoperative immunoadsorption treatment. A more detailed version of this study, with modified tables and figures, has been accepted for publication in Nephrology Dialysis Transplantation.

ABO-incompatible kidney transplantation-proposal of an intensified apheresis strategy for patients with high initial isoagglutinine titers.

Since Tydén's description of ABO-incompatible (ABOi) kidney transplantations based on antigen-specific immunoadsorption (IA) and rituximab (Tydén et al., Am J Transplant 2005;5:145-148), this technique has been successfully adopted by many transplant centers worldwide. The majority of centers strictly adhere to the Swedish protocol and perform IAs with a target volume of 1.5-2 plasma volumes on preoperative days -6, -5, -2, and -1, and postoperative days +3, +6, and +9, respectively. Patients who initially present with an IgG anti-A/B titer higher than 1:128 are not considered suitable candidates for ABOi transplantation by the Swedish protocol. Our center has gone beyond these suggestions and follows a slightly different strategy: We do not exclude patients with initial IgG anti-A/B titers higher than 1:128 and we perform as many preoperative antigen-specific extracorporeal treatments as needed to reach a threshold isoagglutinine titer of 1:4 or less. To intensify isoagglutinine clearance preoperatively, the total target volume per treatment was increased to 2.5-3 plasma volumes. Preconditioning IAs are performed every other day, instead of daily. Postoperatively we perform IAs only, if titers mandate us to do so (Wilpert et al., Nephrol Dial Transplant 2007;22:3048-3051). We report on 11 "high-titer patients" who entered our ABOi kidney transplant program with initial titers of 1:256 or above. Seven of 11 patients (64%) could successfully be transplanted with our modified ABO-apheresis protocol. Four of 11 high-titer patients did not reach target isoagglutinine titers of 1:4 or less and therefore did not undergo transplantation. We conclude that intensified preoperative IA renders a majority of high-titer patients suitable candidates for ABOi kidney transplantation.

Hyperacute rejection of a living unrelated kidney graft.

We present a case report of a 59-year-old man, who received a blood group identical living unrelated kidney graft. This was his second kidney transplantation. Pretransplant T-cell crossmatch resulted negative. B-cell crossmatch, which is not considered a strict contraindication for transplantation, resulted positive. During surgery no abnormalities occurred. Four hours after the transplantation diuresis suddenly decreased. In an immediately performed relaparotomy the transplanted kidney showed signs of hyperacute rejection and had to be removed. Pathological examination was consistent with hyperacute rejection. Depositions of IgM or IgG antibodies were not present in pathologic evaluation of the rejected kidney, suggesting that no irregular endothelial specific antibodies had been involved in the rejection. We recommend examining more closely recipients of second allografts, considering not only a positive T-cell crossmatch but also a positive B-cell crossmatch as exclusion criteria for transplantation.

On-demand strategy as an alternative to conventionally scheduled post-transplant immunoadsorptions after ABO-incompatible kidney transplantation.

BACKGROUND: Since 2001, approximately 100 ABO-incompatible kidney transplantations have been performed in Europe. The standard protocol, employed by most transplant centres, uses rituximab and scheduled pre-emptive antigen-specific immunoadsorption on post-operative days 3, 6 and 9. METHODS: Our centre has performed 22 ABO-incompatible kidney transplantations since 2004, using a different approach; like in Sweden, all patients received immunoadsorptions preoperatively, but instead of scheduling pre-emptive post-transplant immunoadsorptions, we submitted patients to immunoadsorptions post-operatively only, if their isoagglutinine titers (IgG-Anti-A or -B) exceeded certain thresholds. These thresholds were greater than 1 : 8 in the first post-operative week and greater than 1 : 16 in the second post-operative week, respectively. RESULTS: A shorter pre-operative length on dialysis, a blood-type constellation of donor A1/recipient 0 and 9a high initial starting-titer were identified as predictors for post-operative immunoadsorptions. CONCLUSION: Using this on-demand strategy, our data reveal that a titer-dependent protocol reduces costs at no additional risk for the patient.