Friday, November 30, 2012
Impact of immunosenescence on transplant outcome
Aging affects all compartments of the immune response and has a major impact on transplant outcome and organ quality. Although clinical trials in the aging transplant population remain rare, our current understanding of immunosenescence provides a basis for an age-adapted immunosuppression and organ allocation with the goal to optimize utilization and to improve outcomes in older recipients. From a more general perspective, understanding the mechanisms and consequences of immunosenescence will have a broad impact on immune therapies in and beyond transplantation (read more)
Wednesday, November 28, 2012
Antibody-mediated vascular rejection of kidney allografts: a population-based study.
BACKGROUND: Rejection of allografts has always been the major obstacle to
transplantation success. We aimed to improve characterisation of different
kidney-allograft rejection phenotypes, identify how each one is associated with
anti-HLA antibodies, and investigate their distinct prognoses. METHODS: Patients
who underwent ABO-compatible kidney transplantations in Necker Hospital and
Saint-Louis Hospital (Paris, France) between Jan 1, 1998, and Dec 31, 2008, were
included in our population-based study. We assessed patients who provided biopsy
samples for acute allograft rejection, which was defined as the association of
deterioration in function and histopathological lesions. The main outcome was
kidney allograft loss-ie, return to dialysis. To investigate distinct rejection
patterns, we retrospectively assessed rejection episodes with review of graft
histology, C4d in allograft biopsies, and donor-specific anti-HLA antibodies.
FINDINGS: 2079 patients were included in the main analyses, of whom 302 (15%) had
acute biopsy-proven rejection. We identified four distinct patterns of kidney
allograft rejection: T cell-mediated vascular rejection (26 patients [9%]),
antibody-mediated vascular rejection (64 [21%]), T cell-mediated rejection
without vasculitis (139 [46%]), and antibody-mediated rejection without
vasculitis (73 [24%]). Risk of graft loss was 9·07 times (95 CI 3·62-19·7) higher
in antibody-mediated vascular rejection than in T cell-mediated rejection without
vasculitis (p<0·0001), compared with an increase of 2·93 times (1·1-7·9;
P=0·0237) in antibody-mediated rejection without vasculitis and no significant
rise in T cell-mediated vascular rejection (hazard ratio [HR] 1·5, 95% CI
0·33-7·6; p=0·60). INTERPRETATION: We have identified a type of kidney rejection
not presently included in classifications: antibody-mediated vascular rejection.
Recognition of this distinct phenotype could lead to the development of new
treatment strategies that could salvage many kidney allografts. FUNDING: None (read more)
Tuesday, November 27, 2012
Immunologic Challenges in Small Bowel Transplantation
Since the introduction of tacrolimus, small-bowel and multivisceral transplantion has increased to 100–200/year in the United States. The intestine carries more passenger lymphocytes than other organs, and bidirectional trafficking of lymphocytes and other immunocytes begins as soon as the vascular clamp is released. Because of ischemia-reperfusion injury and exposure to ligands for Toll-like receptors from the lumen, the innate immune system of the graft is activated, causing inflammation which must be brought under control by regulatory cells. Inclusion of the liver in the allograft favors graft acceptance, but the mechanism of this effect has not been determined. Anti-HLA and other anti-donor antibodies clearly play a major role in determining the long-term fate of the graft, as reflected in 5-year graft survival. Development of new (de novo) HLA antibodies and/or increases in their titers or function—especially the ability to bind C1q and activate complement increase the risk of graft loss. Monitoring antidonor antibody production and the use of new therapies including complement inhibitors will contribute to increasing success of SBT (read more)
Transplant doctor, Nobel winner Joseph Murray dies at 93
Murray performed the world's first successful kidney transplant.
BOSTON — Dr. Joseph E. Murray, who performed the world's first successful kidney transplant and won a Nobel Prize for his pioneering work, has died at age 93.
Murray suffered a stroke at his suburban Boston home on Thursday, the Thanksgiving holiday, and died at Brigham and Women's Hospital on Monday, hospital spokesman Tom Langford said.
Since the first kidney transplants on identical twins, hundreds of thousands of transplants on a variety of organs have been performed worldwide. Murray shared the Nobel Prize in Physiology or Medicine in 1990 with Dr. E. Donnall Thomas, who won for his work in bone marrow transplants.
"Kidney transplants seem so routine now," Murray told The New York Times after he won the Nobel. "But the first one was like Lindbergh's flight across the ocean."
Murray's breakthroughs did not come without criticism, from ethicists and religious leaders. Some people "felt that we were playing God and that we shouldn't be doing all of these, quote, experiments on human beings," he told The Associated Press in a 2004 interview in which he also spoke out in favor of stem cell research.
In the early 1950s, there had never been a successful human organ transplant. Murray and his associates at Boston's Peter Bent Brigham Hospital, now Brigham and Women's Hospital, developed new surgical techniques, gaining knowledge by successfully transplanting kidneys on dogs. In December 1954, they found the right patients, 23-year-old Richard Herrick, who had end-stage kidney failure, and his identical twin, Ronald Herrick.
Because of their identical genetic background, they did not face the biggest problem with transplant patients, the immune system's rejection of foreign tissue.
After the operation, Richard had a functioning kidney transplanted from Ronald. Richard lived another eight years, marrying a nurse he met at the hospital and having two children.
"Post-operatively the transplanted kidney functioned immediately with a dramatic improvement in the patient's renal and cardiopulmonary status," Murray said in his Nobel lecture. "This spectacular success was a clear demonstration that organ transplantation could be life-saving."
Murray performed more transplants on identical twins over the next few years and tried kidney transplants on other relatives, including fraternal twins, learning more about how to suppress the immune system's rejection of foreign tissue. One patient who received a kidney transplant from a fraternal twin in 1959, plus radiation and a bone marrow transplant to suppress his immune response, lived for 29 more years.
But it was the development of drugs to suppress the body's immune response, a less radical approach than radiation, that made real breakthroughs in transplants possible. In 1962, Murray and his team successfully completed the first organ transplant from an unrelated donor. The 23-year-old patient, Mel Doucette, received a kidney from a man who had died.
Murray continued a long career in plastic surgery, his original specialty, and transplants. He was guided by his own deep religious convictions.
"Work is a prayer," he told the Harvard University Gazette in 2001. "And I start off every morning dedicating it to our Creator."
Murray told the Journal of the American Medical Association in 2004 that he continued to get letters from patients he had helped years earlier and from relatives of those who died during the early efforts.
"They often say ... that they are happy to have played some small part in the eventual success of organ transplants," he said, praising the courage of his patients and their families.
Murray was honored at the 2004 Transplant Games, for athletes who have received organ transplants, along with Ronald Herrick, the man who had donated a kidney to his twin brother a half-century earlier.
Murray continued to support and mentor others at Brigham and Women's Hospital after his retirement, hospital president Dr. Elizabeth Nabel said. An exhibit in the hospital's library housing his Nobel Prize, she said, is framed by his own words: "Service to society is the rent we pay for living on this planet."
Murray's interest in transplants developed during his time in the Army during World War II when he was assigned to Valley Forge General Hospital in Pennsylvania while awaiting overseas duty. The hospital performed reconstructive surgery on troops who had been injured in battle.
The burn patients, who were often treated with skin grafts from other people, intrigued Murray.
"The slow rejection of the foreign skin grafts fascinated me," Murray wrote in his autobiography for the Nobel Prize ceremony. "How could the host distinguish another person's skin from his own?"
The hospital's chief of plastic surgery, Col. James Barrett Brown, had performed skin grafts on civilians and noticed that the closer the donor and recipient were related, the slower the tissue was rejected. A skin graft between identical twins had taken permanently.
Murray said that was "the impetus" for his study of organ transplantation.
Murray was ever the optimist and kept on his desk a quotation, "Difficulties are opportunities," his son Rick Murray said.
"It reflects the unwavering optimism of a great man who was generous, curious, and always humble," Rick Murray said in a statement released by the hospital (original source)
BOSTON — Dr. Joseph E. Murray, who performed the world's first successful kidney transplant and won a Nobel Prize for his pioneering work, has died at age 93.
Murray suffered a stroke at his suburban Boston home on Thursday, the Thanksgiving holiday, and died at Brigham and Women's Hospital on Monday, hospital spokesman Tom Langford said.
Since the first kidney transplants on identical twins, hundreds of thousands of transplants on a variety of organs have been performed worldwide. Murray shared the Nobel Prize in Physiology or Medicine in 1990 with Dr. E. Donnall Thomas, who won for his work in bone marrow transplants.
"Kidney transplants seem so routine now," Murray told The New York Times after he won the Nobel. "But the first one was like Lindbergh's flight across the ocean."
Murray's breakthroughs did not come without criticism, from ethicists and religious leaders. Some people "felt that we were playing God and that we shouldn't be doing all of these, quote, experiments on human beings," he told The Associated Press in a 2004 interview in which he also spoke out in favor of stem cell research.
In the early 1950s, there had never been a successful human organ transplant. Murray and his associates at Boston's Peter Bent Brigham Hospital, now Brigham and Women's Hospital, developed new surgical techniques, gaining knowledge by successfully transplanting kidneys on dogs. In December 1954, they found the right patients, 23-year-old Richard Herrick, who had end-stage kidney failure, and his identical twin, Ronald Herrick.
Because of their identical genetic background, they did not face the biggest problem with transplant patients, the immune system's rejection of foreign tissue.
After the operation, Richard had a functioning kidney transplanted from Ronald. Richard lived another eight years, marrying a nurse he met at the hospital and having two children.
"Post-operatively the transplanted kidney functioned immediately with a dramatic improvement in the patient's renal and cardiopulmonary status," Murray said in his Nobel lecture. "This spectacular success was a clear demonstration that organ transplantation could be life-saving."
Murray performed more transplants on identical twins over the next few years and tried kidney transplants on other relatives, including fraternal twins, learning more about how to suppress the immune system's rejection of foreign tissue. One patient who received a kidney transplant from a fraternal twin in 1959, plus radiation and a bone marrow transplant to suppress his immune response, lived for 29 more years.
But it was the development of drugs to suppress the body's immune response, a less radical approach than radiation, that made real breakthroughs in transplants possible. In 1962, Murray and his team successfully completed the first organ transplant from an unrelated donor. The 23-year-old patient, Mel Doucette, received a kidney from a man who had died.
Murray continued a long career in plastic surgery, his original specialty, and transplants. He was guided by his own deep religious convictions.
"Work is a prayer," he told the Harvard University Gazette in 2001. "And I start off every morning dedicating it to our Creator."
Murray told the Journal of the American Medical Association in 2004 that he continued to get letters from patients he had helped years earlier and from relatives of those who died during the early efforts.
"They often say ... that they are happy to have played some small part in the eventual success of organ transplants," he said, praising the courage of his patients and their families.
Murray was honored at the 2004 Transplant Games, for athletes who have received organ transplants, along with Ronald Herrick, the man who had donated a kidney to his twin brother a half-century earlier.
Murray continued to support and mentor others at Brigham and Women's Hospital after his retirement, hospital president Dr. Elizabeth Nabel said. An exhibit in the hospital's library housing his Nobel Prize, she said, is framed by his own words: "Service to society is the rent we pay for living on this planet."
Murray's interest in transplants developed during his time in the Army during World War II when he was assigned to Valley Forge General Hospital in Pennsylvania while awaiting overseas duty. The hospital performed reconstructive surgery on troops who had been injured in battle.
The burn patients, who were often treated with skin grafts from other people, intrigued Murray.
"The slow rejection of the foreign skin grafts fascinated me," Murray wrote in his autobiography for the Nobel Prize ceremony. "How could the host distinguish another person's skin from his own?"
The hospital's chief of plastic surgery, Col. James Barrett Brown, had performed skin grafts on civilians and noticed that the closer the donor and recipient were related, the slower the tissue was rejected. A skin graft between identical twins had taken permanently.
Murray said that was "the impetus" for his study of organ transplantation.
Murray was ever the optimist and kept on his desk a quotation, "Difficulties are opportunities," his son Rick Murray said.
"It reflects the unwavering optimism of a great man who was generous, curious, and always humble," Rick Murray said in a statement released by the hospital (original source)
Wednesday, November 21, 2012
Fecal microbiota transplantation: past, present and future
PURPOSE OF REVIEW: Fecal microbiota transplantation (FMT) re-establishes a balanced intestinal flora with resultant cure of recurrent Clostridium difficile infection (RCDI). FMT has also been used to treat other gastrointestinal (GI) diseases including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and chronic constipation and a variety of non-GI disorders. The purpose of this review is to discuss the intestinal microbiotaand FMT treatment of GI and non-GI diseases.
RECENT FINDINGS: It is known that an imbalanced intestinal microbiota predisposes to CDI, IBD and IBS. The complex role of intestinal microbiotato maintain health, however, is a newer concept that is being increasingly studied. The microbiome plays an important role in cellular immunity and energy metabolism and has been implicated in the pathogenesis of non-GI autoimmune diseases, chronic fatigue syndrome, obesity and even some neuropsychiatric disorders.
SUMMARY: FMT is a highly effective cure for RCDI, but increased knowledge of the intestinal microbiota in health maintenance, as well as controlled trials of FMT in a wide range of disorders are needed before FMT can be accepted and applied clinically (read more)
RECENT FINDINGS: It is known that an imbalanced intestinal microbiota predisposes to CDI, IBD and IBS. The complex role of intestinal microbiotato maintain health, however, is a newer concept that is being increasingly studied. The microbiome plays an important role in cellular immunity and energy metabolism and has been implicated in the pathogenesis of non-GI autoimmune diseases, chronic fatigue syndrome, obesity and even some neuropsychiatric disorders.
SUMMARY: FMT is a highly effective cure for RCDI, but increased knowledge of the intestinal microbiota in health maintenance, as well as controlled trials of FMT in a wide range of disorders are needed before FMT can be accepted and applied clinically (read more)
Microcirculation Inflammation Associates With Outcome in Renal Transplant Patients With De Novo Donor-Specific Antibodies
In renal transplant patients with de novo donor-specific antibodies (dnDSA) we studied the value of microcirculation inflammation (MI; defined by the addition of glomerulitis (g) and peritubular capillaritis (ptc) scores) to assess long-term graft survival in a retrospective cohort study. Out of all transplant patients with standard immunological risk (n = 638), 79 (12.4%) developed dnDSA and 58/79 (73%) had an indication biopsy at or after dnDSA development. Based on the MI score on that indication biopsy patients were categorized, MI0 (n = 26), MI1 + 2 (n = 21) and MI ≥ 3 (n = 11). The MI groups did not differ significantly pretransplantation, whereas posttransplantation higher MI scores developed more anti-HLA class I + II DSA (p = 0.011), showed more TCMR (p < 0.001) and showed a trend to C4d-positive staining (p = 0.059). Four-year graft survival estimates from time of indication biopsy were MI0 96.1%, MI1 + 2 76.1% and MI ≥ 3 17.1%; resulting in a 24-fold increased risk of graft failure in the MI ≥ 3 compared to the MI0 group (p = 0.003; 95% CI [3.0–196.0]). When adjusted for C4d, MI ≥ 3 still had a 21-fold increased risk of graft failure (p = 0.005; 95% CI [2.5–180.0]), while C4d positivity on indication biopsy lost significance. In renal transplant patients with de novo DSA, microcirculation inflammation, defined by g + ptc, associates with graft survival (read more).
Renal Transplantation in Systemic Amyloidosis—Importance of Amyloid Fibril Type and Precursor Protein Abundance
Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty-nine percent of patients with end-stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A-I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post-RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history (read more)
Tuesday, November 13, 2012
Solid phase detection of C4d-fixing HLA antibodies to predict rejection in high immunological risk kidney transplant recipients
Protocols for recipient desensitization may allow for successful kidney transplantation across major immunological barriers. Desensitized recipients, however, still face a considerable risk of antibody-mediated rejection (AMR), which underscores the need for risk stratification tools to individually tailor treatment. Here, we investigated whether solid phase detection of complement-fixing donor-specific antibodies (DSA) has the potential to improve AMR prediction in high-risk transplants. The study included 68 sensitized recipients of deceased donor kidney allografts who underwent peritransplant immunoadsorption for alloantibody depletion (median cytotoxic panel reactivity: 73%; crossmatch conversion: n = 21). Pre and post-transplant sera were subjected to detection of DSA-triggered C4d deposition ([C4d]DSA) applying single-antigen bead (SAB) technology. While standard crossmatch and [IgG]SAB testing failed to predict outcomes in our desensitized patients, detection of preformed [C4d]DSA (n = 44) was tightly associated with C4d-positive AMR [36% vs. 8%, P = 0.01; binary logistic regression: odds ratio: 10.1 (95% confidence interval: 1.6–64.2), P = 0.01]. Moreover, long-term death-censored graft survival tended to be worse among [C4d]DSA-positive recipients (P = 0.07). There were no associations with C4d-negative AMR or cellular rejection. [C4d]DSA detected 6 months post-transplantation were not related to clinical outcomes. Our data suggest that pretransplant SAB-based detection of complement-fixing DSA may be a valuable tool for risk stratification (read more)
Effect of HLA-Matching Recipients to Donor Noninherited Maternal Antigens on Outcomes after Mismatched Umbilical Cord Blood Transplantation for Hematologic Malignancy
Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non–NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT (read more)
Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation
Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT (read more)
Double Haploidentical Hematopoietic Stem Cell Transplantation Results in Successful Engraftment of Bone Marrow from Both Donors without Graft-versus-Host or Graft-versus-Graft Effects
We established double-haploidentical (DH) hematopoietic stem cell transplantation (HSCT) murine models to explore competitive engraftment, graft-versus-graft effect and graft-versus-host disease (GVHD). T cell–depleted (TCD) bone marrow (BM) cells from B6SJF1 (donor 1 [D1]) and B6D2F1 (donor 2 [D2]) mice achieved >90% donor engraftment when transplanted into B6CBAF1 mice. B6CBAF1 recipients survived without evidence of GVHD when undergoing HSCT with TCD-BM from 2 haploidentical donors, D1 and D2. DH-HSCT recipients had significantly higher leukocyte and neutrophil counts than single-haploidentical HSCT recipients from either D1 or D2. DH recipients consistently showed successful mixed chimerism in both BM and spleen. Two other DH-HSCT models, B6D2F1 + C3D2F1→B6C3F1 and B6CBAF1 + B6SJLF1→B6D2F1, showed similar engraftment patterns. Low-dose T cell infusion from both D1 and D2 increased the degree of early engraftment of the respective donors in BM and spleen; however, this early engraftment pattern did not determine long-term engraftment dominance. In the long term, minimally engrafted D1 BM recovered and comprised >50% of all donor- derived B, T, and natural killer cells. We conclude that early BM engraftment is determined by donor T cell immunodominance, but long-term engraftment is related to the engraftment potential of stem cells after DH-HSCT (read more)
Friday, November 9, 2012
Profiteering threatens the altruism of tissue donation
Tissue donation is not as tightly regulated as organ donation worldwide, and some recent court cases are casting a shadow over this most altruistic of acts (read more)
Cardiac Troponin T Before and After Kidney Transplantation: Determinants and Implications for Posttransplant Survival
Pretransplant cardiac troponin T(cTnTpre) is a significant predictor of survival postkidney transplantation. We assessed correlates of cTnT levels pre- and posttransplantation and their relationship with recipient survival. A total of 1206 adult recipients of kidney grafts between 2000 and 2010 were included. Pretransplant cTnT was elevated (≥0.01 ng/mL) in 56.4%. Higher cTnTpre was associated with increased risk of posttransplant death/cardiac events independent of cardiovascular risk factors. Elevated cTnTpre declined rapidly posttransplant and was normal in 75% of recipients at 3 weeks and 88.6% at 1 year. Elevated posttransplant cTnT was associated with reduced patient survival (cTnT3wks: HR = 5.575, CI 3.207–9.692, p < 0.0001; cTnT1year: 3.664, 2.129–6.305, p < 0.0001) independent of age, diabetes, pretransplant dialysis, heart disease and allograft function. Negative/positive predictive values for high cTnT3wks were 91.4%/50% respectively. Normalization of cTnT posttransplant was associated with reduced risk. Variables related to elevated cTnT posttransplant included pretransplant diabetes, older age, time on dialysis, high cTnTpre and lower graft function. Patients with delayed graft function and those with GFR < 30 mL/min at 3 weeks were more likely to have an elevated cTnT3wks and remained at high risk. When allografts restore sufficient kidney function cTnT normalizes and patient survival improves. Lack of normalization of cTnT posttransplant identifies a group of individuals with high risk of death/cardiac events (read more)
Workshop report: a website for the antibody-defined HLA epitope registry
http://epregistry.ufpi.br
The concept that HLA antibodies are specific for epitopes rather than HLA antigens is important not only for the determination of mismatch acceptability for sensitized patients but also for a better understanding of the antibody response to an HLA mismatch. Numerous publications describe epitope-specific antibodies, but there is no standardized information about the repertoire of clinically relevant HLA epitopes. Under auspices of the 16th IHIW, we have developed a website-based registry of antibody-verified HLA epitopes. Epitope notations are based on HLA molecular modelling of amino acid residues in polymorphic sequence positions. Informative epitope-specific antibodies had been induced by a transplant, transfusion or pregnancy and were monoclonal antibodies or eluates of sera absorbed with single HLA alleles. Antibody reactivity was determined in binding assays with single-allele panels. Antibody producer/immunizer HLA types enhanced the characterization of specific epitopes. The Registry also includes epitopes described in original research publications. Based on the extent of antibody reactivity information, we assigned epitope status as confirmed (well documented) or provisional (more data are needed). At present, the Registry has 69 HLA-ABC, 53 DRB1/3/4/5, 17 DQ, 8 DP and 22 MICA antibody-verified epitopes and will be updated on a quarterly basis. Laboratories worldwide continue to submit data about previously unreported antibody-specific epitopes. For each epitope, the website shows its amino acid composition and HLA alleles that share the epitope. Links show antibody reactivity patterns, sensitization information and references. Other links show molecular modelling of corresponding structural epitopes and polymorphic residue information for epitope-carrying alleles. The website will also have a link to epitope frequency information in different populations. Search functions will list mismatched epitopes on mismatched alleles for selected HLA types. The HLA Epitope Registry will become a valuable resource for researchers interested in HLA compatibility at the epitope level and investigating antibody responses to HLA mismatches (read more)
The concept that HLA antibodies are specific for epitopes rather than HLA antigens is important not only for the determination of mismatch acceptability for sensitized patients but also for a better understanding of the antibody response to an HLA mismatch. Numerous publications describe epitope-specific antibodies, but there is no standardized information about the repertoire of clinically relevant HLA epitopes. Under auspices of the 16th IHIW, we have developed a website-based registry of antibody-verified HLA epitopes. Epitope notations are based on HLA molecular modelling of amino acid residues in polymorphic sequence positions. Informative epitope-specific antibodies had been induced by a transplant, transfusion or pregnancy and were monoclonal antibodies or eluates of sera absorbed with single HLA alleles. Antibody reactivity was determined in binding assays with single-allele panels. Antibody producer/immunizer HLA types enhanced the characterization of specific epitopes. The Registry also includes epitopes described in original research publications. Based on the extent of antibody reactivity information, we assigned epitope status as confirmed (well documented) or provisional (more data are needed). At present, the Registry has 69 HLA-ABC, 53 DRB1/3/4/5, 17 DQ, 8 DP and 22 MICA antibody-verified epitopes and will be updated on a quarterly basis. Laboratories worldwide continue to submit data about previously unreported antibody-specific epitopes. For each epitope, the website shows its amino acid composition and HLA alleles that share the epitope. Links show antibody reactivity patterns, sensitization information and references. Other links show molecular modelling of corresponding structural epitopes and polymorphic residue information for epitope-carrying alleles. The website will also have a link to epitope frequency information in different populations. Search functions will list mismatched epitopes on mismatched alleles for selected HLA types. The HLA Epitope Registry will become a valuable resource for researchers interested in HLA compatibility at the epitope level and investigating antibody responses to HLA mismatches (read more)
Wednesday, November 7, 2012
Chronic GVHD is associated with inferior relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors
Chronic GVHD (cGVHD) has been associated with reduced risk of relapse after allo-SCT for onco-hematological disease due to a graft-vs-malignancy effect. Here we retrospectively analyzed a series of 802 adult patients transplanted from unrelated donors and found that cGVHD was associated with significantly lower relapse and that the limited form was associated with a survival advantage: hazard ratio for OS=0.63 (0.46–0.87); P=0.004; this was due to combination of relapse reduction and similar non-relapse mortality with respect to patients without cGVHD. Importantly, the graft-vs-malignancy effect observed here did not differ when PBSC or BM were used as stem cell source, thus suggesting that the protective effect of limited cGVHD is similar after PBSC- or BM-based transplantation. These findings could have practical implications and suggest no qualitative difference between cGVHD occurring after transplantation performed with different stem cell sources (read more)
Is it time to revisit our current hematopoietic progenitor cell quantification methods in the clinic?
In the clinical practice of hematopoietic SCT, the minimum numbers of cells required for a successful engraftment are defined on the basis of their CD45 and CD34 expression profiles. However, the quantity of earlier progenitors or CD34-positive cells at different differentiation stages within stem cell grafts is not generally taken into consideration. During the last decade, various teams have quantified the number of cells expressing various combinations of CD34, CD38, CD133, CD90 co-expression and/or aldehyde dehydrogenase functional capacity using flow cytometry. Some of these studies resulted in the greater appreciation that combinations of these Ags were associated with varied myeloid, erythroid and platelet engraftment rates whereas others showed that the relative absence or presence of these markers could define cells responsible for either short- or long-term engraftment. These findings were also extended to differences between progenitor cell populations found within BM vs peripheral or cord-blood grafts. Cells harvested from donors are also generally frozen and stored; thawed cells have variable levels of viability and functional capacity based on the time tested post thaw, which also can be assessed by flow cytometry. Finally, flow cytometry has the potential for analysis of cells carrying a mesenchymal stem cell phenotype, which may be quiescent within some of the stem cell products. This review will address the need for stem cell subpopulation quantification and summarize existing published data to identify some Ags and functional characteristics that can be applicable to daily clinical practice (read more).
Pretransplantation Soluble CD30 Level As a Predictor of Acute Rejection in Kidney Transplantation: A Meta-Analysis
Background: The question of whether high pretransplantation soluble CD30 (sCD30) level can be a predictor of kidney transplant acute rejection (AR) is under debate. Herein, we performed a meta-analysis on the predictive efficacy of sCD30 for AR in renal transplantation.
Methods: PubMed (1966–2012), EMBASE (1988–2012), and Web of Science (1986–2012) databases were searched for studies concerning the predictive efficacy of sCD30 for AR after kidney transplantation. After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of sCD30 were pooled. A summary receiver operating characteristic curve was used to represent the overall test performance.
Results: Twelve studies enrolling 2507 patients met the inclusion criteria. The pooled estimates for pretransplantation sCD30 in prediction of allograft rejection risk were poor, with a sensitivity of 0.70 (95% confidence interval (CI), 0.66–0.74), a specificity of 0.48 (95% CI, 0.46–0.50), a positive likelihood ratio of 1.35 (95% CI, 1.20–1.53), a negative likelihood ratio of 0.68 (95% CI, 0.55–0.84), and a diagnostic odds ratio of 2.07 (95% CI, 1.54–2.80). The area under curve of the summary receiver operating characteristic curve was 0.60, indicating poor overall accuracy of the serum sCD30 level in the prediction of patients at risk for AR.
Conclusions: The results of the meta-analysis show that the accuracy of pretransplantation sCD30 for predicting posttransplantation AR was poor. Prospective studies are needed to clarify the usefulness of this test for identifying risks of AR in transplant recipients (read more)
Methods: PubMed (1966–2012), EMBASE (1988–2012), and Web of Science (1986–2012) databases were searched for studies concerning the predictive efficacy of sCD30 for AR after kidney transplantation. After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of sCD30 were pooled. A summary receiver operating characteristic curve was used to represent the overall test performance.
Results: Twelve studies enrolling 2507 patients met the inclusion criteria. The pooled estimates for pretransplantation sCD30 in prediction of allograft rejection risk were poor, with a sensitivity of 0.70 (95% confidence interval (CI), 0.66–0.74), a specificity of 0.48 (95% CI, 0.46–0.50), a positive likelihood ratio of 1.35 (95% CI, 1.20–1.53), a negative likelihood ratio of 0.68 (95% CI, 0.55–0.84), and a diagnostic odds ratio of 2.07 (95% CI, 1.54–2.80). The area under curve of the summary receiver operating characteristic curve was 0.60, indicating poor overall accuracy of the serum sCD30 level in the prediction of patients at risk for AR.
Conclusions: The results of the meta-analysis show that the accuracy of pretransplantation sCD30 for predicting posttransplantation AR was poor. Prospective studies are needed to clarify the usefulness of this test for identifying risks of AR in transplant recipients (read more)
Non-HLA Antibodies Targeting Vascular Receptors Enhance Alloimmune Response and Microvasculopathy After Heart Transplantation
Background: Non–human leukocyte antigen antibodies (Abs) targeting vascular receptors are implicated in the pathogenesis of renal allograft vascular rejection and in progressive vasculopathy in patients with systemic sclerosis.
Methods: We prospectively tested in 30 heart transplant recipients the impact of Abs directed against endothelin-1 type A (ETAR) and angiotensin II type 1 receptors (AT1R, cell-enzyme–linked immunosorbent assay) at time of transplantation and during the first posttransplantation year on cellular and Ab-mediated rejection (immunohistochemistry, C3d, and immunoglobulins) and microvasculopathy in endomyocardial biopsy.
Results: Cellular rejection, Ab-mediated rejection, and microvasculopathy was found in 40% and 13%, 57% and 18%, and 37% and 40% of biopsies at 1 month and 1 year posttransplantation, respectively. Maximum levels of AT1R and ETAR Abs were higher in patients with cellular (16.5±2.6 vs. 9.4±1.3; P=0.021 and 16.5±2.5 vs. 9.9±1.9; P=0.041) and Ab-mediated rejection (19.0±2.6 vs. 10.0±1.3; P=0.004 and 19.4±2.7 vs. 9.0±1.7; P=0.002), as compared with patients who had no rejection. Patients with elevated AT1R Abs (53% [16/30]) or ETAR Abs (50% [15/30]; pretransplantation prognostic rejection cutoff >16.5 U/L) presented more often with microvasculopathy (both, 67% vs. 23%; P=0.048) than patients without.
Conclusions: Elevated levels of AT1R and ETAR Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation (read more).
Methods: We prospectively tested in 30 heart transplant recipients the impact of Abs directed against endothelin-1 type A (ETAR) and angiotensin II type 1 receptors (AT1R, cell-enzyme–linked immunosorbent assay) at time of transplantation and during the first posttransplantation year on cellular and Ab-mediated rejection (immunohistochemistry, C3d, and immunoglobulins) and microvasculopathy in endomyocardial biopsy.
Results: Cellular rejection, Ab-mediated rejection, and microvasculopathy was found in 40% and 13%, 57% and 18%, and 37% and 40% of biopsies at 1 month and 1 year posttransplantation, respectively. Maximum levels of AT1R and ETAR Abs were higher in patients with cellular (16.5±2.6 vs. 9.4±1.3; P=0.021 and 16.5±2.5 vs. 9.9±1.9; P=0.041) and Ab-mediated rejection (19.0±2.6 vs. 10.0±1.3; P=0.004 and 19.4±2.7 vs. 9.0±1.7; P=0.002), as compared with patients who had no rejection. Patients with elevated AT1R Abs (53% [16/30]) or ETAR Abs (50% [15/30]; pretransplantation prognostic rejection cutoff >16.5 U/L) presented more often with microvasculopathy (both, 67% vs. 23%; P=0.048) than patients without.
Conclusions: Elevated levels of AT1R and ETAR Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation (read more).
No Evidence for Recipient-Derived Hepatocytes in Serial Biopsies of Sex-Mismatched Liver Transplants
Background: Bone marrow–derived hematopoietic stem cells (BM-HSCs) have been shown to act as source for hepatic regeneration in rodent models; however, their ability to participate in human liver regeneration remains controversial. The aim of this study was to investigate the origin of hepatocytes in sex-mismatched cases of orthotopic liver transplantation in longitudinally performed liver biopsies.
Methods: Paraffin-embedded liver biopsy samples of 14 patients after sex-mismatched (female-to-male) liver transplantation were investigated. Biopsies were taken at multiple time points and subjected to histologic examination. Immunohistochemical staining with a hepatocyte-specific antibody and fluorescent in situ hybridization for visualization of Y chromosomes were performed to analyze the presence of recipient-derived hepatocytes.
Results: We analyzed 30 liver biopsy samples ranging from 1 week to more than 3 years after transplantation. There was no evidence for recipient-derived hepatocytes in liver transplants at any time point. We were able to detect recipient-specific chromosomal status in inflammatory cells within the liver but not within hepatocytes. Results were independent of liver injury at the time of biopsy, caused by hepatitis C recurrence or rejection episodes.
Conclusions: Our results show no evidence for involvement of BM-HSCs in liver regeneration after orthotopic liver transplantation. We think that recipient BM-HSC–derived hepatocyte repopulation is a very rare event at best and is not of clinical relevance (read more)
Methods: Paraffin-embedded liver biopsy samples of 14 patients after sex-mismatched (female-to-male) liver transplantation were investigated. Biopsies were taken at multiple time points and subjected to histologic examination. Immunohistochemical staining with a hepatocyte-specific antibody and fluorescent in situ hybridization for visualization of Y chromosomes were performed to analyze the presence of recipient-derived hepatocytes.
Results: We analyzed 30 liver biopsy samples ranging from 1 week to more than 3 years after transplantation. There was no evidence for recipient-derived hepatocytes in liver transplants at any time point. We were able to detect recipient-specific chromosomal status in inflammatory cells within the liver but not within hepatocytes. Results were independent of liver injury at the time of biopsy, caused by hepatitis C recurrence or rejection episodes.
Conclusions: Our results show no evidence for involvement of BM-HSCs in liver regeneration after orthotopic liver transplantation. We think that recipient BM-HSC–derived hepatocyte repopulation is a very rare event at best and is not of clinical relevance (read more)
Saturday, November 3, 2012
Cold ischemic time is critical in outcomes of expanded criteria donor renal transplantation
The outcomes of expanded criteria donor (ECD) kidneys have been reported to be inferior compared with standard criteria donor (SCD) kidneys. However, the graft survival rate of ECD is not so inferior to SCD in Korea. The purposes of this study were to compare the outcomes of ECD kidneys with SCD kidneys and identify the influencing factors. We retrospectively studied 143 deceased donor transplants from August 2006 to June 2010. The patients were divided into SCD (n = 117) and ECD (n = 26) by UNOS criteria. The one- and three-yr graft survival rates of SCD and ECD (99.1% and 94.4% vs. 100% and 92.9%, respectively, p = 0.15) were not significantly different between groups. The mean cold ischemic time (CIT) was 3.8 ± 2.2 h. When compared the outcome of ECD kidneys with data reported by Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients (OPTN/SRTR) (one- and three-yr graft survival rate: 86.7% and 73.2%), the graft survival rate of our center was superior. In OPTN/SRTR data, transplant with CIT shorter than 11 h was only 20%. The outcomes of ECD grafts are outstanding and comparable with SCD grafts in our center, and the only distinguishing factor is markedly short CIT. Finishing the allocation before organ recovery and immediate operations after recovery could shorten the CIT (read more)
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