CD4+ T cell-mediated rejection of major histocompatibility complex class I-disparate grafts: A role for alloantibody

Experimental studies of the T cell requirement for rejection of class I major histocompatibility complex (MHC)-disparate grafts have generated controversy over both the autonomy of CD8⁺ T cells and the mechanism whereby CD4⁺ T cells are able to independently mediate rejection. In this study of rejection of RT1A^a class I MHC-disparate rat cardiac and skin allografts by high-responder PVG RT1^u recipients, we show that elimination of CD8⁺ T cells [by anti-CD8 monoclonal antibody (mAb) administration in vivo] fails to prolong graft survival, whereas partial depletion of CD4⁺ T cells (by anti-CD4 mAb treatment) markedly delays rejection of class I-disparate heart grafts, and marginally prolongs survival of skin grafts. Anti-CD4-treated PVG-RT1^u athymic nude rats reconstituted with CD8⁺ T cells failed to reject class I-disparate skin grafts for several weeks and eventual rejection correlated with re-emergence of a small number of donor derived CD4⁺ T cells. Conversely, anti-CD8-treated nude rats reconstituted with CD4⁺ T cells alone rapidly rejected class I-disparate skin grafts. Passive transfer of anti-class I immune serum to anti-CD4-treated euthymic recipients promptly restored their ability to specifically reject a class I-disparate heart graft. Similarly, passive transfer of immune serum to PVG-RT1^u nude rats bearing skin allografts caused destruction of class I-disparate but not third-party grafts. These results demonstrate that CD4⁺ T cells are both necessary and sufficient to cause rejection of class I-disparate heart and skin grafts in this model and that CD4⁺ T cell-dependent alloantibody plays a decisive role in effecting rejection.     

Loss of tolerance to a maternal kidney transplant is selective for HLA class II: evidence from trans-vivo DTH and alloantibody analysis

We studied late graft rejection in a patient who had received a kidney transplant 9–10 years earlier from his mother and who had been off all immunosuppressive drugs for 7 years at the time of graft rejection onset. The mother differed for one HLA-A (A3) and one HLA-B (B62) antigen but had only a subtype mismatch at the HLA-DRβ1 locus (donor: DRβ1*1104; recipient: DRβ1*1102). A gradual rise in serum creatinine from 1.8 to 2.0 mg/dl at year 9 prompted a biopsy, which was negative for rejection (focal infiltrates but no tubulitis). Ten months later the patient’s creatinine had risen to > 3.4 mg/dl, and a second biopsy revealed extensive tubulitis, cellular rejection, and glomerular sclerosis. Sonicates of donor leukocytes triggered no delayed-type hypersensitivity (DTH) response above background (PBMC only) in the patient’s peripheral blood leukocytes obtained prior to year 9. A gradual recovery of antidonor DTH response between year 9 and 10 closely paralleled the change from tolerant to rejection status. Antidonor antibody was also undetectable in serum prior to year 9, but a donor-reactive antibody did develop at year 10.2 shortly after the peak of DTH response. The serum level of soluble donor HLA class I B62 antigen rose > 10-fold over prerejection level at the time of the biopsy-proven rejection, suggesting a possible trigger for both the cellular and humoral immune response. Nonetheless, we found no evidence for the de-velopment of humoral or cellular immunity to maternal HLA class I. Instead, DTH analysis of memory T cells of the patient obtained after rejection showed that a single maternal HLA DRβ1*1104 allopeptide, differing by two amino acids in sequence from the peptide of the recipient (DRβ1*1102), stimulated a strong memory DTH response. Similarly, we found an anti-HLA class II donor-specific antibody in serum that appeared to be crossreactive with DRβ1*1104 and DRβ1*1101 but not with the recipient DRβ1*1102 antigen. The data support the idea of a profound unresponsive state at both the cellular (DTH) and humoral level toward maternal HLA class I antigens that was not reversed even during late cellular rejection, despite the release of high levels of soluble HLA class I. Furthermore, the data suggest that DTH recovery was a close correlate of the onset of rejection and this “indirect” alloresponse, like the anti-donor alloantibody response that followed, was directed not to noninherited maternal HLA-A,B antigens but to the maternal HLA DRβ1*1104 subtype.     

Autonomic Correlates of Depression and Clinical Improvement Following Electroconvulsive Shock Therapy

Electrodermal responses (EDRs) and heart rate (HR) were recorded during a variety of tasks from 20 hospitalized depressed patients before and after a series of electroconvulsive shock treatments (ECTs). The depressed patients, compared to nondepressed controls during the pre-ECT test, exhibited lower skin conductance levels, smaller phasic skin conductance responses with longer latencies, higher tonic HR, and smaller HR changes to stimuli. This response pattern suggests a complex state of “environmental rejection” coupled with “low arousal” in the depressed patients. Certain EDR measures were related to the severity of depressive symptomatology while tonic HR was related to the agitation/retardation symptoms. Patients who subsequently responded well following ECT were more like the controls on certain pre-treatment measures than those who failed to respond favorably. There were little EDR or HR changes following ECT and what changes did occur were unrelated to differences in clinical improvement. It was suggested that, despite temporary clinical improvement following ECT, depressed patients have a chronic affective disorder which is reflected in the EDR and HR measures.     

Hypertension risk factors and cardiovascular reactivity to mental stress in young men

Hypertension risk may be associated with increased pressor response to mental stress. However, studies using family history as a predictor of reactivity have obtained mixed results. We assessed cardiovascular responses to mental arithmetic stress (a 5-min serial subtraction task) in male medical students (n = 220) at three levels of hypertension risk based on parental history and the subject's systolic blood pressure (SBP): low (SBP < 125 mm Hg and 0 or 1 hypertensive parent), moderate (resting SBP ≥ 125 mm Hg or 2 hypertensive parents), or high (resting SBP ≥ 125 mm Hg and 1 or 2 hypertensive parents). High risk men showed the greatest blood pressure responses ( + 22/ + 16 mm Hg), while moderate and low-risk groups showed correspondingly smaller responses ( + 17/ + 13 and + 14/ + 11 mm Hg, p's < 0.02). Family history alone did not predict differential reactivity. This study replicates and extends our previous work suggesting the importance of using both family history and resting blood pressure level in determining future risk for hypertension in studies of cardiovascular reactivity in relation to hypertension risk in males.     

Prolactin levels in paternal striped mouse (Rhabdomys pumilio) fathers

Paternal behavior is associated with an increase in prolactin levels in fish, birds and mammals, including rodents. The striped mouse (Rhabdomys pumilio) from southern Africa shows highly developed paternal care. We investigated whether striped mouse fathers have higher prolactin levels than nonfathers, and whether there is a relationship between tactile stimulation with pups and prolactin secretion in fathers. We measured serum prolactin in 42 male striped mice assigned to one of four different experimental groups (single males, paired males, fathers housed with mother and pups, and fathers separated from their family by a wire-mesh partition). Our results revealed no increases in prolactin levels in fathers, and fathers with tactile contact with pups did not have higher prolactin levels than the fathers that were prevented from making tactile contact with pups. In contrast, experienced males had higher prolactin levels than inexperienced males. Male striped mice are polygynous in nature, living in groups, with three breeding females, and are permanently associated with pups during the breeding season. In a field study, males had higher prolactin levels during the breeding season than during the nonbreeding season. Thus, prolactin secretion in the polygynous striped mouse might be regulated by environmental stimuli, whereas social stimuli might be important for monogamous species. This is the first study to demonstrate seasonal changes in prolactin levels in a free-living male mammal.     

Role of HLA molecular mismatch in clinical practice

To date, traditional pre-transplant risk factors have failed to provide accurate risk stratification in transplantation. As a result, the practice of precision medicine remains elusive, resulting in a one-size-fits-all therapeutic approach for most patients. However, recent advancements in the understanding of HLA molecules at the molecular level have revitalized interest in HLA mismatch assessment. This review discusses HLA molecular mismatch as a potential prognostic and predictive biomarker available at the time of transplantation and answers some of the common questions and critiques of this approach. We highlight the retrospective data that supports single molecule risk categorization and explore the next steps required to evaluate its potential in clinical practice.     

Cross-national study of perceived parental rearing behaviour in healthy subjects from Australia, Denmark, Italy, The Netherlands and Sweden: pattern and level comparisons

Samples of healthy subjects from Australia, Denmark, Italy, The Netherlands and Sweden completed the EMBU, a Swedish questionnaire aimed at assessing the experience of parental rearing practices. For the purpose of comparison three factors - "emotional warmth", "rejection" and "overprotection" - obtained in a previous factor analytic study, have been used. The most pronounced differences occurred between the Dutch and the Swedish sample on the one hand, and the Italian and Australian sample on the other, with the Danish sample in between. Differences in perceived parental rearing should be considered when comparing personality characteristics and/or psychopathological conditions in subjects from different countries.     

Perceived parental rearing practices in depressed patients in relation to social class

The occurrence of possible differences in rearing practices related to social class has been investigated in a series of 125 depressed patients by means of a special inventory - the EMBU - constructed by our group. Three factors derived from the EMBU in the course of previous studies: "rejection", "emotional warmth", "overprotection" have been taken into account. The rearing practices experienced by subjects belonging to different social classes did not differ concerning "emotional warmth". On the other hand, subjects belonging to the higher social classes scored their parents higher on the variables "rejection" and "overprotection". Since "emotional warmth" proved in an earlier study to discriminate between depressives and healthy controls, it is concluded that the difference cannot have been biased by possible differences in social class.     

Development and Validation of the Sexual and Reproductive Empowerment Scale for Adolescents and Young Adults

PurposeWe developed and validated a measure that assesses the latent construct of sexual and reproductive empowerment among adolescents and young adults. A specific measure for this group is critical because of their unique life stage and circumstances, which often includes frequent changes in sexual partners and involvement from parents in decision-making.MethodsAfter formative qualitative research, a review of the literature, and cognitive interviews, we developed 95 items representing nine dimensions of sexual and reproductive empowerment. Items were then fielded among a national sample of young people aged 15–24 years, and those who identified as sexually active completed a 3-month follow-up survey. We conducted psychometric analysis and scale validation.ResultsExploratory factor analysis on responses from 1,117 participants resulted in the Sexual and Reproductive Empowerment Scale for Adolescents and Young Adults, containing 23 items captured by seven subscales: comfort talking with partner; choice of partners, marriage, and children; parental support; sexual safety; self-love; sense of future; and sexual pleasure. Validation using logistic regression demonstrated that the subscales were consistently associated with sexual and reproductive health information and access to sexual and reproductive health services measured at baseline and moderately associated with the use of desired contraceptive methods at 3-month follow-up.ConclusionsThe Sexual and Reproductive Empowerment Scale for Adolescents and Young Adults is a new measure that assesses young people’s empowerment regarding sexual and reproductive health. It can be used by researchers, public health practitioners, and clinicians to measure sexual and reproductive empowerment among young people.