Beata Nowakowska

The influence of non‐HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes

Non‐HLA antibodies (Abs) targeting vascular receptors are thought to have an impact on renal transplant injury. Anti‐angiotensin II type 1‐receptor‐activating antibodies (anti‐AT1R) have been mentioned to stimulate a severe vascular rejection, but the pretransplant screening has not been introduced yet. The aim of our study was to assess the incidence and importance of anti‐AT1R antibodies and their influence on renal transplant in the 1st year of observation. We prospectively evaluated the presence of anti‐AT1R antibodies in 117 consecutive renal transplant recipients in pre‐ and post‐transplant screening. Anti‐AT1R antibodies were observed in 27/117 (23%) of the analyzed recipients already before transplantation. The function of renal transplant was considerably worse in anti‐AT1R(+) group. The patients with anti‐AT1R Abs >9 U/ml lost their graft more often. Biopsy‐proven AR was described in 4/27 (15%) pts in the anti‐AT1R(+) group and 13/90 (14.4%) in the anti‐AT1R(−) group, but more severe cases of Banff IIB or antibody‐mediated rejection (AMR) were more often observed in anti‐AT1R (+) 4/27 (15%) vs. 1/90 (1.1%) in anti‐AT1R(+) (P = 0.009). Patients with anti‐AT1R Abs level >9 U/ml run a higher risk of graft failure independently of classical immunological risk factors. The recipients with anti‐AT1R Abs developed more severe acute rejections described as IIB or AMR in Banff classification. More recipients among the anti‐AT1R‐positive ones lost the graft. Our study suggests monitoring of anti‐AT1R Abs before renal transplantation for assessment of immunologic risk profiles and the identification of patients highly susceptible to immunologic events, graft failure, and graft loss.

The impact of non-HLA antibodies directed against endothelin-1 type A receptors (ETAR) on early renal transplant outcomes.

BACKGROUND Non-HLA antibodies (Abs) targeting vascular receptors are considered to have an influence on renal transplant injury. Anti-endothelin-1 type A receptor (anti-ETAR) antibodies were associated with cellular and antibody-mediated rejection and early onset of vasculopathy in heart transplant patients but their role in renal transplantation remains unclear. The aim of our study was to assess the incidence and importance of anti-ETAR antibodies and their impact on renal transplant during the first year observation. METHODS We evaluated the presence of anti-ETAR antibodies in 116 consecutive renal transplant recipients in pre- and post-transplant screening (before and in 1st, 3rd, 6th, 12th month after transplantation). Additionally, we assessed the presence of anti-HLA antibodies. Anti-ETAR antibodies were assayed by ELISA. The diagnosis of acute rejection was based on the Banff criteria. RESULTS Anti-ETAR antibodies were observed in 55 (47.4%) of the analyzed recipients before transplantation. The function of renal transplant was significantly worse in the anti-ETAR(+) group compared to the anti-ETAR(-) group during the first post-transplant year. One month after transplantation the serum creatinine in anti-ETAR (+) patients (pts) was 1.86±0.8mg/dl and 1.51±0.5 in anti-ETAR(-) pts (p=0.009). Twelve months after transplantation the difference between the groups was still observed 1.70±0.7 vs. 1.40±0.4 (p=0.04). Biopsy proven acute rejection was recognized in 8/55 (14.5%) in ETAR(+) and 9/61 (14.8%) in ETAR(-) patients but cases with mild to severe intimal arteritis (v1-v3) were more often observed in patients with the presence of anti-ETAR Abs 4/55 (7.2%) comparing with 1/61 (1.6%) in anti-ETAR(-) patients. The anti-ETAR antibody levels varied at different measurement intervals during the one-year follow-up. CONCLUSIONS The presence of anti-ETAR antibodies is associated with a worse renal transplant function during the first 12months after transplantation. Including anti-ETAR antibodies in the diagnostics of renal transplant recipient immune status should be considered to provide comprehensive assessment of humoral alloimmunity.

Weak association of anti-sperm antibodies and strong association of familial cryptorchidism/infertility with HLA-DRB1polymorphisms in prepubertal Ukrainian boys

BackgroundCryptorchidism is a frequent syndrome occurring in 1-2% of males within the first year of age. Autoimmune reactions, particularly directed to testicular elements and/or spermatozoa have been found to be often associated with cryptorchidism. Therefore we investigated in this study the frequency of HLA class II alleles in order to recognize possible genetic predisposition for antisperm antibodies development in prepubertal boys with diagnosed cryptorchidism in Caucasoid population.MethodsSixty prepubertal boys with cryptorchidism and sixty healthy boys were examined for anti-sperm antibodies by indirect immunobead test as well as for their HLA-DRB1 and -DQB1 alleles using DNA obtained from peripheral blood leukocytes. The typing of HLA-DRB1 and -DQB1 was performed by using PCR-SSP low resolution method.ResultsAllele frequencies of HLA-DRB1 and HLA-DQB1 did not differ between boys with cryptorchidism and control boys. However, weakly significant differences in DRB1*04 (p corrected = 0.0475) and DQB1*06 (p corrected = 0.0385) were seen between cryptorchid patients with and without AsA, but none of these two patient groups differed significantly in HLA class II frequencies from controls except for AsA-negatives and HLA-DQB1*06 (p corrected = 0.0247). On the other hand, comparison of cryptorchid boys with familial cryptorchidism and/or infertility to control boys revealed highly significant (p corrected = 0.0006) difference in HLA-DRB*11 frequency, whereas boys with sporadic cryptorchidism did not differ from control. A much weaker, but still significant difference in DRB*11 frequency was also observed between boys with bilateral cryptorchidism and controls (p corrected = 0.037), whereas patients with unilateral cryptorchidism were not different from control in frequency of any HLA-DRB1 or -DQB1 allele tested.ConclusionsPredisposition to produce anti-sperm antibodies seems to be only weakly associated with HLA class II genes, although this question requires further study on much larger population sample. It is plausible that familial and sporadic cryptorchidism may present distinct genetic background. The same may, to lower extent, apply to bilateral and unilateral cryptorchidism.

Opioid receptors in psoriatic skin: relationship with itch

Psoriasis is an inflammatory immunogenetic skin disease, often accompanied by itch. Opioid receptors are known regulators of itch sensation in the central nervous system. In the brain, μ-opioid receptors may potentiate itch, while activation of κ-opioid receptors may reduce or even alleviate itch; however, the role of opioid receptors in itch perception in the skin is poorly understood. To further elucidate the role of opioid receptors in the neurobiology of psoriatic itch, punch biopsies of non-lesional and lesional skin of patients with psoriasis and healthy controls were studied. Real-time polymerase chain reaction and immunofluorescence microscopy were used to detect opioid receptor genes and protein expression, respectively. The OPRK1/κ-opioid receptor pathway was found to be downregulated in lesional skin of psoriasis, correlating positively with itch sensation. In contrast, the OPRM1/μ-opioid receptor system was uniformly expressed by epidermal keratinocytes in all analysed groups. These findings suggest that imbalance of epidermal opioid receptors may result in disordered neuroepidermal homeostasis in psoriasis, which could potentiate transmission of itch.

DOUBLE HAPLOIDENTICAL TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS IN A BOY WITH MYELODYSPLASTIC SYNDROME

A 12-year-old boy with myelodysplastic syndrome underwent a double transplantation of hematopoietic progenitor cells from his haploidentical brother. After conditioning with busulfan, cyclophosphamide, and Vepesid, the first bone marrow transplantation was performed using 3.53 x 10(6)/kg of CD34+ cells. Initial engraftment was followed by graft rejection. The second conditioning consisted of melphalan and anti-thymocyte globulin. The boy was then transplanted with 5.15 x 10(6)/kg of CD34+ cells, harvested from bone marrow (BM) and peripheral blood. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine A + short methotrexate. Hematological recovery was rapid and stable. Acute GvHD 1 degree (skin) resolved after 2 weeks of steroid treatment. A relapse occurred on day +140. At that time NK cells decreased from 20 to 7% with the lowest CD4+/CD8+ ratio, 0.07. Just after relapse, the percentage of cytokine-induced killer cells (CIK-CD3+CD56+) dropped from 3.34 to 0.1%. CsA treatment was stopped and the patient received T cell (CD3+ cells) add-back four times on days +146, +199, +234, and +262 in doses of 0.5 x 10(5), 1.0 x 10(5), 2.0 x 10(5), and 4.0 x 10(5)/kg, respectively. No acute GvHD occurred. Additionally, bone marrow biopsy before the second add-back showed complete remission. Analysis of lymphocyte subsets before the fourth add-back showed the highest values of CD4+, NK, and CIK cells and also the highest CD4+/CD8+ ratio.

Lack of detectable fetal microchimerism in psoriasis vulgaris lesions and in non-affected skin in spite of its presence in peripheral blood CD34-positive and CD34-negative cells

Microchimerism is defined as a stable presence of low numbers of cells derived from a different individual due to cell transfer between twins or between mother and fetus during pregnancy.