[Immune-mediated thrombotic thrombocytopenic purpura and susceptible HLA alleles].

Thrombotic thrombocytopenic purpura (TTP) is an extremely rare and fatal thrombotic disorder characterized by impaired enzyme activity of von Willebrand factor cleaving protease, also known as ADAMTS13. Immune-mediated TTP (iTTP) is an acquired form of TTP caused by the production of auto-antibodies against ADAMTS13. The pathophysiology of autoimmune disorders is multifactorial, with several human leukocyte antigen (HLA) alleles identified as a genetic risk factor for autoimmune diseases known as susceptible HLA. In the early 2010s, three distinct European groups revealed that DRB1*11 is one of the most susceptible alleles in acquiring iTTP among Caucasians based on HLA typing data. Several in silico predictions for allele-restricted ADAMTS13 epitopes against T cells are made in this context, followed by an in vitro validation employing mass spectrometry using eluted peptides and T-cell assays. However, similar analyses in a genetically distinct Japanese population have not yet been conducted. We used next-generation sequencing to perform HLA typing for 52 Japanese patients with iTTP from 19 institutes. Our detailed analysis revealed that the specific allele DRB1*08:03 was identified as a genetic risk factor for iTTP in Japanese patients, but there were no statistically significant differences in the allele frequency of DRB1*11 between iTTP and healthy controls.

Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation.

The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.

HLA-DP mismatch and CMV reactivation increase risk of aGVHD independently in recipients of allogeneic stem cell transplant.

HLA-DP mismatched allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with increased risk of aGVHD and decreased risk of relapse with no effects on overall survival (OS). It has been proposed that CMV-reactivation induces expression of HLA-DP molecules on GVHD target tissues by releasing inflammatory cytokines. We hypothesized that the increased GVHD incidence in HLA-DP mismatched allo-SCTs correlates with recipient CMV serostatus or CMV reactivation. In addition, CMV reactivation is associated with increased risk of GVHD with an unknown mechanism. Here, we analyzed the association between HLA-DPB1 and CMV reactivation on cumulative incidence of aGVHD and relapse as well as OS in 613 patients with AML and MDS who underwent matched related or unrelated allo-HCT at MD Anderson Cancer Center from 2005 to 2011. In multivariable analysis, HLA-DPB1 mismatching was associated with increased risk of aGVHD (hazard ratio (HR): 1.53, P < 0.001) independent of CMV serostatus and CMV reactivation. Additionally, HLA-DPB1 mismatching was associated with decreased risk of relapse and no effect on OS. CMV reactivation increased risks of aGVHD (HR: 5.82, P < 0.001) independent of HLA-DP mismatching with no effect on relapse or OS. In conclusion, our data suggests that HLA-DPB1 mismatching and CMV reactivation increase risk of aGVHD independently.

HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia: Results From the Microtransplantation Interest Group.

IMPORTANCE: The outcome of older patients with acute myeloid leukemia (AML) remains unsatisfactory. Recent studies have shown that HLA-mismatched microtransplant could improve outcomes in such patients. OBJECTIVE: To evaluate outcomes in different age groups among older patients with newly diagnosed AML who receive HLA-mismatched microtransplant. DESIGN, SETTING, AND PARTICIPANTS: This multicenter clinical study included 185 patients with de novo AML at 12 centers in China, the United States, and Spain in the Microtransplantation Interest Group. Patients were divided into the following 4 age groups: 60 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 85 years. The study period was May 1, 2006, to July 31, 2015. EXPOSURES: Induction chemotherapy and postremission therapy with cytarabine hydrochloride with or without anthracycline, followed by highly HLA-mismatched related or fully mismatched unrelated donor cell infusion. No graft-vs-host disease prophylaxis was used. MAIN OUTCOMES AND MEASURES: The primary end point of the study was to evaluate the complete remission rates, leukemia-free survival, and overall survival in different age groups. Additional end points of the study included hematopoietic recovery, graft-vs-host disease, relapse rate, nonrelapse mortality, and other treatment-related toxicities. RESULTS: Among 185 patients, the median age was 67 years (range, 60-85 years), and 75 (40.5%) were female. The denominators in adjusted percentages in overall survival, leukemia-free survival, relapse, and nonrelapse mortality are not the sample proportions of observations. The overall complete remission rate was not significantly different among the 4 age groups (75.4% [52 of 69], 70.2% [33 of 47], 79.1% [34 of 43], and 73.1% [19 of 26). The 1-year overall survival rates were 87.7%, 85.8%, and 77.8% in the first 3 age groups, which were much higher than the rate in the fourth age group (51.7%) (P = .004, P = .008, and P = .04, respectively). The 2-year overall survival rates were 63.7% and 66.8% in the first 2 age groups, which were higher than the rates in the last 2 age groups (34.2% and 14.8%) (P = .02, P = .03, P < .001, and P < .001, respectively). The 1-year cumulative incidences of nonrelapse mortality were 10.2%, 0%, 3.4%, and 26.0% in the 4 age groups and 8.1% in all patients. The median times to neutrophil and platelet recovery were 12 days and 14 days after induction chemotherapy, respectively. Five patients had full or mixed donor engraftment, and 30.8% (8 of 26) of patients demonstrated donor microchimerism. Two patients (1.1%) developed severe acute graft-vs-host disease. CONCLUSIONS AND RELEVANCE: Microtransplant achieved a high complete remission rate in AML patients aged 60 to 85 years and higher 1-year overall survival in those aged 60 to 74 years.

[Non eligibility criteria for hematopoietic stem cell donors: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Critères de non-qualification des donneurs des cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

The evolution of HLA typing and transplantation techniques makes it easier to identify a donor for hematopoietic stem cell (HSC) transplantation. This activity, strongly regulated by regulatory or normative texts, implies in addition biological, medical, para-medical and sometimes psychological evaluations. The benefit/risk discussion is complicated because it must take into account the benefit/risk ratio for the recipient, and the donor risk. No Evidence-Based Medicine data is available and serious events are very rare situations. Biovigilance declarations and their analysis are of fundamental importance. Certain obvious and definite contraindications could be detected very early in the process. It is important to assess whether a risk factor or pathology contributes to increasing the risk associated with collection. In case of recipient risk, the situation should be discussed with the patient team. These recommendations focus on adult peripheral blood HSC donors. They refer to donor information, confidentiality of exchanges, the impact of moral or material pressures, declarations of biovigilance, collegiality and traceability of difficult decisions, desirable experience and training for doctors in charge, use of expert advice informed by an explicit exchange on the possible risks, parsimony of therapeutic interventions and minimization of risks for the donor. We also recommend creation, availability and use by the community of tools and documents (registries, questionnaires, synthetic recommendations, feedback, and collegial qualification meetings) useful for practice.

Subclinical rejection in stable positive crossmatch kidney transplant patients: incidence and correlations.

We reviewed 116 surveillance biopsies obtained approximately 1, 3, 6 and 12 months posttransplantation from 50 +XM live donor kidney transplant recipients to determine the frequency of subclinical cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). Subclinical CMR was present in 39.7% of the biopsies at 1 month and >20% at all other time points. The presence of diffuse C4d on biopsies obtained at each time interval ranged from 20 to 30%. In every case, where histological and immunohistological findings were diagnostic for AMR, donor-specific antibody was found in the blood, challenging the long-held belief that low-level antibody could evade detection due to absorption on the graft. Among clinical factors, only recipient age was associated with subclinical CMR. Clinical factors associated with subclinical AMR were recipient age, positive cytotoxic crossmatch prior to desensitization and two mismatches of HLA DR 51, 52 and 53 alleles. Surveillance biopsies during the first year post-transplantation for these high-risk patients uncover clinically occult processes and phenotypes, which without intervention diminish allograft survival and function.

HLA-A24: factor de riesgo en retinopatía diabética proliferante / HLA-A24: risk factor in proliferante diabetic retinopathy

Objetivo: La retinopatía diabética proliferante (RDP) se caracteriza por pérdida de la visión en la población joven. Está bien establecido que el antígeno leucocitario humano (HLA)-A24 es un factor de riesgo para la pérdida total de las células‚ del páncreas. Nuestro objetivo es estudiar la asociación del HLA-A24 con la RDP. Material y método: Se estudió un grupo de pacientes con RDP (n= 95) y un grupo control (n= 60). A todos se les determinó el HLA-A24 mediante técnicas hibridación molecular. Resultados: El grupo control mostró menos frecuencia de HLA-A24 que el grupo con RDP (p= 0,043). El HLA-A24 se asoció a retinopatía diabética proliferante (OR = 5,4; 95% CI= 3,2-7,6; p< 0,001). Conclusiones: El HLA-A24 no es un factor de protección para la retinopatía diabética proliferante, es un factor de riesgo para desarrollarla

Objective: Proliferative diabetic retinopathy (PDR) is characterized by a progressive visual impairment in young people. Human leucocyte antigen (HLA)- A24 is a well-established factor associated with the pancreatic islets of Langerhans lost in this process. Our aim was to study further the relationship of the HLA-A24 associated with PDR. Materials and methods: We evaluated a group of patients with PDR (n=95) and a healthy control group (n= 60). HLA-A24 for each participant in the study was determined by molecular hybridization techniques. Results: The control group showed a lower frequency of HLA-A24 compared with the PDR group (p = 0.043). HLA-A24 was associated with PDR (OR = 5.4; 95% CI= 3.2-7.6; p< 0.001). Conclusions: HLA-A24 is not a protective factor for PDR, but is a risk factor of its development

Risk factors for developing human herpesvirus 6 (HHV-6) reactivation after allogeneic hematopoietic stem cell transplantation and its association with central nervous system disorders.

We prospectively evaluated the incidence of human herpesvirus 6 (HHV-6) DNAemia after allogeneic hematopoietic stem cell transplantation (HSCT) using quantitative plasma real-time polymerase chain reaction. Of 46 recipients of bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT) from related (n = 11) or unrelated donors (n = 22), and cord blood transplantation (CBT) from unrelated donors (n = 13), 22 (47.8%) developed HHV-6 DNAemia. HHV-6 DNA levels ranged from 200 to 200,000 copies/mL of plasma, and HHV-6 DNAemia was observed significantly more frequently after CBT than after BMT/PBSCT (92.3% vs 30.3%; P < .001). Multivariate analyses identified CBT (vs BMT/PBSCT), HLA mismatches between recipient and donor, and low anti-HHV-6 IgG titer before transplantation as the only risk factors for developing HHV-6 DNAemia. Three patients developed central nervous system (CNS) disorders with detectable HHV-6 DNA in the cerebrospinal fluid; all of these patients simultaneously developed HHV-6 DNAemia. These results suggest that HHV-6 DNAemia is frequently observed after allogeneic HSCT, especially in patients with the aforementioned risk factors. Thus, together with the assessment of risk factors, monitoring of HHV-6 DNAemia could be a useful asset in diagnosing HHV-6-associated CNS disorders.

Successful treatment of thrombocytopenia and hemolytic anemia with IvIG in a patient with lupus-like syndrome after mismatched related PBSCT.

Hematopoietic stem cell transplantation (HSCT) is a treatment option for autoimmune diseases but can also cause clinical features similar to those of autoimmune diseases. In some of these cases the autoimmune-like condition is associated with autoimmune cytopenia, a complication that can be unresponsive to established treatment strategies and which may be fatal. The majority of cases reported on immune hemolytic anemia have been of alloimmune origin due to ABO red blood cell antigen incompatibilities between donor and recipient. We now report a patient with a lupus-like syndrome, presenting with severe thrombocytopenia and hemolytic anemia 9 months after HLA-mismatch, ABO compatible-related PBSCT who experienced no response to high-dose steroids, but who had a sustained response to repeated IvIG therapy.

Conditioning regimens for allogeneic stem cell transplants.

In addition to providing cytoreduction at myeloablative dose intensity, conditioning regimens for allogeneic transplantation are designed to immunosuppress the recipient to permit donor lymphohematopoietic engraftment and thereby establish a graft-versus-malignancy effect. Increased confidence in the potency of this allogeneic graft-versus-malignancy effect, together with the need to reduce dose intensity to make transplantation safer and more widely applicable in older patients, has led to a conceptual revolution in conditioning regimen design. Novel nonmyeloablative transplant conditioning treatments have low regimen-related toxicity and low transplant-related mortality. The transplants confer a graft-versus-malignancy effect in myeloid and lymphoid malignancies and in metastatic renal cell cancer. Future prospects are for low toxicity conditioning regimens combined with specific antileukemia or antitumor intensification with radioconjugated or unmodified antibodies and the application of highly immunosuppressive but low toxicity conditioning regimens for mismatched transplants.

Faster neutrophil and platelet engraftment, but no differences in acute GVHD or survival, using peripheral blood stem cells from related and unrelated donors, compared to bone marrow.

In this retrospective study, 23 recipients of peripheral blood progenitor cells (PBPC) were compared to 23 recipients of bone marrow (BM). The donors were 12 HLA-A-B-DR identical siblings and 11 HLA-A-B-DR identical unrelated donors in the PBPC and BM groups, respectively. Diagnoses in the PBPC group were CML seven, AML, nine, ALL three, lymphoma one, myeloma two and aspartylglucosaminuria (AGU) one. The median age was 40 (5-55) years. The BM group was matched for diagnosis, age, conditioning therapy, GVHD prophylaxis and G-CSF treatment after BMT. A higher number of MNC (P<0.001), CD34+ (P = 0.05), CD3+ (P<0.001) and CD56+ (P<0.001) cells in the graft, a reduced number of platelet transfusions (P = 0.03) and a significant hastening of neutrophil and platelet recovery were seen in the PBPC group compared to the BM group. In logistic regression analysis, the following factors were important for engraftment of ANC >0.5 x 10(9)/l: peripheral blood progenitor cell transplantation (PBPCT) (P = 0.003) and mononuclear cells (MNC) > or =2.5 x 10(8)/kg recipient in the graft (above median) (P = 0.009) in univariate analysis. For recovery of platelets >30 x 10(9)/l: PBPCT (P = 0.03) and HLA-identical sibling donors (P = 0.05) were significant in multivariate analysis. A trend towards a lower incidence of bacteremia was seen in the PBPC group, ie 22 vs 48% (P = 0.06) in the BM group. GVHD, TRM and survival did not differ between the two groups.

Genetic aspects of rheumatoid arthritis.

Studies on the population of patients with rheumatoid arthritis and families with multiple cases of rheumatoid arthritis have provided definite evidence that susceptibility to the disease is determined both by genetic factors associated with alleles of the major histocompatibility complex as well as environmental factors. The development of seropositive, but not seronegative rheumatoid arthritis is associated with the presence in an individual of the Ia alloantigen HLA-DR4. This association is common to all major ethnic groups. Some evidence exists that this association is stronger in patients that have more severe disease but this fact requires further study. The fraction of the seropositive patients with rheumatoid arthritis that lack HLA-DR4 has not been well characterized. The occurrence of certain untoward side effects of therapy is influenced by the presence of HLA-DR2 or HLA-DR3. Family studies emphasize the association with HLA-DR4, and indicate that the disease has a dominant mode of inheritance with partial penetrance. The inheritance of susceptibility appeared, at least in some families, to be primarily associated with the inheritance of HLA-DR4 itself and not well explained by a hypothetical disease susceptibility gene present at low frequency and associated in linkage disequilibrium with a HLA-DR4 marker. However, in others different mechanisms appeared more likely. A model of two MHC genes involved in influencing disease susceptibility is postulated. Speculations concerning the primary disease mechanism are presented involving abnormalities of IR genes, general immune regulation, and factors outside of the immune system.