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It was found earlier that the effect of the uvrE- mutation on the yield of recombinants formed via RecF pathway of recombination was mainly due to the decreased viability of the recB-C-sbcB-uvrE- recipient. The results of the present paper show the uvrE- and recL- mutations reduce the recipient ability of the recB-C- sbcB- strains to the same extent. We were unable to find any evidence for complementation between the recL- and uvrE- mutations in transient as well as in stable uvrE-/recL- merozygotes. The recL152 as well as the uvrE502 mutation is lethal for the strains deficient in DNA polymerase I. Both recL- and uvrE- mutations reduce in the recB-C- sbcB- strains the probability of inheritance of the proximal non-selective donor markers as well as selective markers located close to the leading end of the donor chromosome. The former effect however could not be completely due to the latter.
Conjugal mating experiments were performed between donor strains of Vibrio cholerae carrying the vibrio sex plasmid P and recipient strains lacking the P plasmid. Donor and recipient genotypes differed with respect to toxinogenicity (tox), nutritional requirements, and antibiotic susceptibilities. Recombinants carrying selected donor and recipient markers were produced at low frequencies in conjugal matings. Mapping of tox markers was accomplished by scoring for the frequency of coinheritance of the donor tox allele with selected and unselected donor markers. Four independently isolated tox markers were analyzed. Each of these four tox markers was shown to be linked to the his-1 site in linkage group I on the genetic map of V. cholerae. In matings between a recipient strain carrying the tox-1 marker and donor strains carrying either tox-2, tox-3, or tox-4, all selected his+ recombinants remained nontoxinogenic. Matings between multiply marked strains demonstrated that the position of tox-1 with respect to other genetic loci in linkage group I is as follows: met-2--trp-1--asp-1--nal-1--his-1--tox-1. These findings demonstrate that a chromosomal determinant linked to his-1 in linkage group I on the genetic map of V. cholerae is essential for toxinogenesis and suggest that tox-1,tox-2, tox-3, and tox-4 may be alleles of a single tox gene.
A critical factor limiting the availability of histocompatible platelet transfusions for alloimmunized, thrombocytopenic patients is the large pool of HLA-typed donors needed to procure platelets perfectly matched for HLA antigens. We have, therefore, investigated the effectiveness of platelets obtained from donors having lesser degrees of histocompatibility. In 421 transfusions administered to 59 alloimmunized patients who were refractory to "random donor" platelets, it was found that platelets mismatched for 1 or 2 "cross-reactive" HLA antigens were in most instances as effective in increasing circulating platelet levels as perfectly matched platelets. A significant number of patients also responded to platelets from donors selectively mismatched for non-cross-reactive HLA antigens. The latter group had a significantly reduced frequency of the antigen HLA-A2 (13%) in comparison to the total patient population (49%). Use of donors whose HLA antigens are serologically cross-reactive with those of alloimmunized patients provides approximately 10 times as many prospective donors as does selection based on matching for HLA and simplifies the procurement of hemostatically effective platelets for such patients.
Survival of 51Cr-labeled allogenic platelets was repeatedly measured in rabbits previously sensitized by weekly intradermal injections of platelets from donor animals. When values of recovery and survival time were reduced to very low levels, a massive infusion of platelets from randomly selected donor rabbits was given and survival study was repeated. A large increase in platelet survival and recovery was seen in every experiment. Similar results, although of lesser magnitude, were obtained with the infusion of platelets made nonviable by prolonged storage and, also, of lyophilized platelets. A significant increase in life span and recovery of allogenic platelets was also observed in two patients with thrombocytopenia due to aplastic anemia, severely allosensitized to platelets. After one massive infusion of viable or of nonviable platelets, survival and hemostatic effectiveness of subsequently infused allogenic platelets was greatly improved in both patients. Experimental blockade of the RES and titration of the serum alloantibody by the 14C-serotonin release method demonstrated that the favorable effect of the massive platelet infusions was due to the temporary adsorption of the alloantibody in the circulation of the sensitized animals. This two-step procedure of one massive infusion of viable, nonviable or lyophilized allogenic platelets followed by a small infusion of freshly collected platelets may be of practical value in arresting hemorrhage in selected thrombocytopenic patients refractory to all types of available donor platelets because of severe and complex alloimmunization.
Twenty-two living related renal transplant operations have been performed at Prince Henry's Hospital over the last seven years. Donors have been accepted for nephrectomy only after exhaustive examination of their health and serach for renal disease. The one and three year graft survival rates have been 85% and 64% respectively. Only two recipients have died, and recipient morbidity has been low. Donors have not suffered any serious complication from nephrectomy. It is concluded that living related renal transplantation has many advantages over cadaveric renal transplantation and is a relatively safe procedure for the donor, provided that rigid criteria are used in donor selection.
This report describes the sensitisation of latex particles and the use of this reagent on the Autotape system to select blood donations containing greater than or equal to 4 IU/ml of tetanus toxoid antibody. Plasma containing tetanus toxoid antibodies is processed to provide immunoglobulin for passive protection against tetanus. The techniques used for screening include immunoelectrophoresis [3], tetanus toxoid sensitised latex particles [5], haemagglutination [1] and automated haemagglutination [6]. The technique used by the Sheffield Regional Transfusion Centre until recently, was immunoelectrophoresis, selecting donors with 4 or more IU/ml. The Autotape system, previously described for brucellosis [4] and syphilis testing [2], provides a system for automated slide testing and a 5-min tetanus toxoid coated latex test has been developed to select suitable donations for the production of specific immunoglobulin.
Ankylosing spondylitis is diagnosed once or twice in each 1000 males and one tenth as frequently in females, but the true prevalence is unknown. Indentification of genetic marker, HL-A W27, for susceptible persons has provided a tool facilitating epidemiologic studies and allowing identification of "control" populations without the marker. Evaluation by postal questionnaires, and pelvic radiography of 78 HL-A 27W-positive blood donors selected from a group of apparently healthy subjects revealed 14 who satisfied the criteria for definite ankylosing spondylitis. The prevalence was similar in both sexes. One hundred and twenty-six W27-negative controls matched for race, sex, and age failed to yield a single case. For a person of either sex with HL-A W27, there appears to be about a 20 per cent chance that ankylosing spondylitis will develop, suggesting a prevalence of 10 to 15 per thousand. Hitherto accepted figures may underestimate the frequency by a factor of 10 to 20.
Outcome in eighty-eight recipients of cadaveric donor renal allografts preserved before implantation by machine perfusion with a solution of human albumin was compared to that for eighty-three recipients of similar kidneys implanted after simple cold storage. Average total ischaemic intervals for machine-perfused and cold-stored kidneys were 18 and 4 1/4 hours, respectively. Machine-perfused kidneys were implanted regardless of perfusion characteristics. Initial function and 1-month and 1-year graft survivals for the machine-perfused group (58%, 85%, 68%, respectively) were either similar or improved compared to those of cold-stored kidneys (58%, 81%, 52%, respectively). Improved 1-year survival for machine-perfused grafts was dependent upon reduced rejection. Careful donor selection and management ensured good machine perfusion of kidneys on 90% of occasions. In the other 10%, despite poor perfusion characteristics, outcome for kidneys was similar to those with good perfusion characteristics. Antilymphocyte globulin treatment reduced rejection whether allografts were machine perfused or not. In the absence of antilymphocyte globulin treatment, machine-perfused kidneys did much better than cold-stored kidneys. Machine perfusion had important advantages and improved the results in kidney-graft recipients.
Human leukocyte antigen (HLA) disparity between donors and recipients is a key determinant triggering intense alloreactivity, leading to a lethal complication, namely, acute graft-versus-host disease (aGVHD), after allogeneic transplantation. Moreover, aGVHD remains a cause of mortality after HLA-matched allogeneic transplantation. Protocols for HLA-haploidentical hematopoietic cell transplantation (haploHCT) have been established successfully and widely applied, further highlighting the urgency of performing panoramic screening of non-HLA variations correlated with aGVHD. On the basis of our time-consecutive large haploHCT cohort (with a homogenous discovery set and an extended confirmatory set), we first delineated the genetic landscape of 1366 samples to quantitatively model aGVHD risk by assessing the contributions of HLA and non-HLA genes together with clinical factors. In addition to identifying multiple loss-of-function (LoF) risk variations in non-HLA coding genes, our data-driven study revealed that non-HLA genetic variations, independent of HLA disparity, contributed the most to the occurrence of aGVHD. This unexpected major effect was verified in an independent cohort that received HLA-identical sibling HCT. Subsequent functional experiments further revealed the roles of a representative non-HLA LoF gene and LoF gene pair in regulating the alloreactivity of primary human T cells. Our findings highlight the importance of non-HLA genetic risk in the new era of transplantation and propose a new direction to explore the immunogenetic mechanism of alloreactivity and to optimize donor selection strategies for allogeneic transplantation.
Effector cells for cell-mediated lysis (CML) were generated by in vitro culture of lymphocytes from selected donors with X-irradiated cells from unrelated subjects who were HLA-D homozygous and matched to the responders for the antigens of the HLA-A and HLA-B regions. By using chromium labeled monocytes as target cells, cytotoxicity was found to correlate with presence of HLA-D region antigens matching those of the stimulating cells. Such CML reactions apparently directed at products of HLA-D, were inhibited by addition of unlabeled monocytes or B lymphocytes. These unlabeled cells had to be matched for HLA-D with the stimulating cells used to generate the effector populations. The results suggested that products of HLA-D, perhaps the DR antigens, were recognized by cytotoxic lymphocytes.
The relationships between immune reactivity after blood transfusions, subsequent kidney allograft survival, and donor selection were studied in dogs. Animals with a high as well as low serological immune reactivity toward antigens contained in blood transfusion were observed. Genetic control of this reactivity or a linkage of this property to DLA, sex, or red blood cell markers inheritance was not apparent in the four beagle families studied. The two recipients with the lowest immune reactivity scores were also found to be the longest survivors after a DLA-mismatched kidney graft. Seven other recipients with higher scores rejected their DLA-mismatched kidneys as rapidly as did untransfused animals. Kidney graft survival was decreased in some recipients of DLA-identical kidneys (n = 5), presumably through sensitization for minor histocompatibility antigens. A normal or an increased survival time of DLA-identical kidneys was found in the remaining animals (n = 6). The majority of these recipients appeared to have a higher than average reactivity in two-stage microcytotoxicity testing. This might have been attributable to the presence of enhancing antibodies. Further studies in preclinical animal models are needed to define the optimal transfusion policy for human patients awaiting a kidney graft.
Kidney transplantation outcomes arise from complex interactions among donor organ quality, recipient susceptibility, and immunologic compatibility, yet conventional clinical risk models explain only a modest fraction of outcome variability. Polygenic risk scores (PRS) offer a promising framework to enhance transplant risk assessment by integrating genome-wide genetic information from both donor and recipient into biologically informed models. This narrative review examines the mechanistic basis for PRS application in kidney transplantation and variant clustering approaches that link polygenic signals to specific biological pathways underlying alloimmunity, fibrosis, and metabolic dysfunction. We compare current PRS construction methodologies, highlighting their respective strengths and limitations in transplant cohorts. Transplant PRS are distinguished from single-genome disease models by their capacity to capture dual-genome interactions, simultaneously quantifying inherited donor organ liability and recipient genetic susceptibility within an integrated framework. This dual-genome architecture requires novel risk stratification paradigms in which combined donor-recipient polygenic profiles inform pretransplant decision-making in ways that neither genome alone can achieve. However, current PRS contribute only incremental variance beyond established clinical predictors, and critical limitations persist, including European ancestry bias, small cohort sizes, incomplete replication, and undefined clinical actionability thresholds. We critically evaluate these implementation barriers and outline future directions for integrating dual-genome PRS with clinical, molecular, and environmental data. The longer-term goal is to advance precision kidney transplantation through applications such as donor selection, immunosuppression tailoring, and individualized posttransplant surveillance. Realizing this potential will require validation in adequately powered, ancestry diverse, prospective transplant cohorts.
In conclusion, then, we would answer the seven questions raised earlier concerning transfer factor as follows: Certianly, as shown by clinical results, it does exist. It does have a definite immunologic effect in humans, boosting cell-mediated immunity, as shown by a rise in the level of active T cells. Its clinical effects have been demonstrated repeatedly, and it should become useful in still other clinical situations as further research provides more effective therapeutic modalities. Transfer factor from selected donors appears to provide prophylaxis against metastasis when administered to osteosarcoma patients with no clinically evident metastases at the time of surgical removal of the primary tumor; whether this treatment is superior to chemotherapeutic prophylaxis is conjectural and controversial. Its mechanism of action has not been demonstrated as yet, although many theories exist. The best evidence is that the effects are both specific and nonspecific. It appears to be produced by T lymphocytes. The exact nature of the substance we call "transfer factor" remains to be elucidated. Further research should provide more conclusive answers to these questions.
Genomic profiling plays a central role in risk stratification and therapeutic decision-making in acute myeloid leukemia (AML), yet the clinical implications of population-specific genomic architectures remain incompletely defined. We conducted a prospective, multicenter study of 603 adults with newly diagnosed AML in Korea, integrating targeted sequencing of 83 recurrently mutated genes with comprehensive clinical annotation across treatment intensities, including allogeneic hematopoietic stem cell transplantation (allo-HSCT). For contextual comparison, genomic profiles were evaluated against the Beat AML cohort. The overall genomic landscape was broadly conserved, supporting shared core disease biology across populations. However, RUNX1::RUNX1T1, CEBPA, GATA2, KIT, and DDX41 mutations were more frequent in the Korean cohort, whereas FLT3 and NPM1 mutations were less common. These differences translated into a distinct distribution of European LeukemiaNet (ELN) 2022 risk categories, with implications for therapeutic stratification. Notably, most DDX41 alterations were germline (3.2%), highlighting the need for systematic germline evaluation with implications for genetic counseling and donor selection. Although unadjusted overall survival appeared longer in the Korean cohort, this difference was not significant after adjustment for key clinical variables. These findings indicate that population-specific genomic distributions reshape the clinical application of risk stratification and support population-aware precision medicine strategies in AML.
Resistance of young chicks and poults to salmonella exposure was substantially increased by early oral administration of intestinal contents or feces from selected adult chickens. Protection was secured also by administering anaerobic broth cultures of intestinal microflora from selected donor birds. Protection, was substantial for 63 days, the longest period tested, although it could be overcome by severe exposure. The protective mechanism appears to be a consequence of competitive exclusion of salmonella by "normal" microflora of the gastrointestinal tract.