The role of KIR genes in hematopoietic stem cell transplantation

Receptori prirodnoubilačkih stanica slični imunoglobulinu (engl. killer cell immunoglobulin-like receptor, KIR) su obitelj inhibicijskih i aktivacijskih receptora ispoljenih na prirodnoubilačkim stanicama (NK), a osnovna funkcija im je regulacija aktivnosti stanica NK. Receptori KIR imaju utjecaj na tijek i ishod transplantacije te su odgovorni za stvaranje aloreaktivnih stanica NK prilikom transplantacije krvotvornih matičnih stanica (TKMS). Kako bi se istražila uloga receptora KIR u imunologiji transplantacijske reakcije, provedeno je temeljno istraživanje polimorfizama i učestalosti gena, genotipova i haplotipova KIR na reprezentativnom uzorku hrvatske populacije (N=125). Retrogradnom analizom 111 bolesnika liječenih TKMS od srodnog i nesrodnog davatelja, istražen je utjecaj gena KIR na čimbenike ishoda TKMS: preživljavanje, GvHD i postizanje punog kimerizma. Dobiveni rezultati ukazuju da ligandi HLA-C skupine C1 i C2 primatelja kao i genotip KIR primatelja i davatelja imaju pozitivan učinak na preživljavanje i pojavu GvHD-a, dok na postizanje punog kimerizma nemaju nikakav učinak.Killer cell immunoglobulin-like receptors (KIR) are family of inhibitory and activatory receptors expressed on natural killer cells (NK) with the basic role of regulation the NK cell activity. KIRs have influence on the hematopoietic stem cell transplantation (HSCT) outcome and are responsible for generating alloreactive NK cells. To explore the KIR gene role in HSCT, we performed the basic investigation of gene polymorphisms and KIR gene, haplotype and genotype frequencies in the group of healthy unrelated individuals (N=125) that represents the Croatian population and serve as a control group in the further studies. The role of KIR genes in HSCT in terms of disease free survival, the intensity of GvHD and chimerism was evaluated by retrograde analyses of 111 patients and their related and unrelated donors. The results showed that the HLA-C ligands and the donor-recipient KIR genotypes have major influence on the survival and GvHD effect, while there is no effect on achieving full chimerism after HSCT

HLA-DPB1 matching in unrelated hematopoietic stem cell transplantation program contributes to a higher incidence of disease relapse

The impact of patient/donor matching for HLA-A, -B, -C, -DRB1 and -DQB1 genes in hematopoietic stem cell transplantation (HSCT) is well-recognized, but typing for additional genes, such as HLA-DPB1, is still controversial. Based on defined T-cell epitope (TCE) groups, all HLA-DPB1 mismatches can be classified as permissive or non-permissive. In this retrospective study we analysed 82 patient-matched unrelated donor (MUD) pairs who underwent HSCT, and explored the impact of HLA-DPB1 matches, permissive and non-permissive mismatches on transplantation outcomes. Patient-MUD pairs matched for HLA-DPB1 alleles in univariate analysis were associated with a significantly higher incidence of disease relapse compared to pairs who were permissive/non-permissive HLA-DPB1 mismatched according to the TCE3 and TCE4 algorithms (P=0.025 and P=0.026, respectively), although the significance was lost in multivariate analysis. The analysis did not reveal any significant influence of HLA-DPB1 alleles on overall survival (OS), non-relapse mortality (NRM) or graft-versus-host disease (GvHD) incidence. In conclusion, our study presents evidence that HLA-DPB1 matching influenced the relapse rate in patients after HSCT so the HLA-DPB1 alleles should be implemented in the MUD search algorithm as a transplantation determinant

Detection of early cardiac allograft vasculopathy in a high-risk transplant patient using optical coherence tomography

Introduction: Cardiac allograft vasculopathy (CAV) is a common cause of late graft failure and mortality in heart transplant recipients. Concentric intimal proliferation that reflects immune-mediated vascular damage in the early post-transplant years is difficult to recognize by conventional coronary angiography. Optical coherence tomography (OCT) is a high resolution intravascular imaging technique that has the potential to identify subtle early vessel wall changes and shape the therapeutic approach that may improve patients’ outcomes. Case report: 68-year-old male patient underwent heart transplantation with positive lymphocyte crossmatch and Luminex that detected anti-HLA class I (A1, A25, B8, B57) donor-specific antibodies with MFI up to 2500. The patient was treated with steroid, antilymphocyte (rATG) induction, tacrolimus, and mycophenolate mofetil, in combination with IVIG and plasmapheresis. Graft function was preserved, biopsies showed no or mild cellular-mediated rejection (1R) with no signs of antibody-mediated rejection (AMR) with negativization of anti-A1 and -A25 antibodies. However, control biopsy after 6 months became positive for AMR. The patient was treated with steroid pulse, IVIG, plasmapheresis, and rituximab. The following biopsies were negative for AMR and the patient remained with preserved graft function. One year after transplantation we performed control coronary angiography with OCT. While coronary angiography was interpreted as normal, control OCT showed significant diffuse intimal thickening with maximal intimal thickness up to 920 μm and intima/media cross-sectional media of ≥1 (Figure 1). This finding prompted a change in therapy with the maximization of statin dose and introduction of everolimus in the maintenance immunosuppressive regimen. Conclusion: This case report indicates the limitation of conventional coronary angiography in the early detection of transplant vasculopathy. OCT is able to establish the diagnosis and trigger specific therapeutic interventions like the introduction of everolimus before vascular changes become visible on conventional coronary angiography and resistant to treatment. Unfortunately, we still lack clearly defined OCT criteria for both diagnosis and treatment, but the progress in this field of transplant cardiology is promising