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The results of this study on the kidney waiting list suggest that denial of donor kidneys to recipients based on HLA antibody specificities detected exclusively in the single‐antigen‐bead assay is not justified. See editorial by Gebel and Bray on page 1951.

In this retrospective registry analysis of kidney transplants, maintenance steroid dose shows a significant association with death due to infection or cardiovascular disease even in patients with good graft outcome in whom steroid treatment would appear to be unnecessary.

Death with a functioning graft remains a major challenge following kidney transplantation. Steroid dosing may be a modifiable risk factor. Collaborative Transplant Study (CTS) data were analyzed to assess the relationship between long-term steroid dose and death with function during years 2–5 posttransplant in 41 953 adult recipients of a deceased-donor kidney transplant during 1995–2010. Steroid dose at year 1 correlated significantly with death with function overall, and with death due to cardiovascular disease or infection (all p < 0.001). In patients with optimal graft function (serum creatinine <130 µmol/L) and no anti-rejection treatment during (a) year 1 (b) years 1 and 2, these significant associations remained (all p < 0.001). The center-specific incidence of steroid withdrawal during year 2 showed a significant inverse association with death due to cardiovascular disease (p < 0.001) or infection (p < 0.001) overall, and within the subpopulation with good graft function and no rejection during year 1 (p = 0.002 and p < 0.001, respectively). Maintenance steroid dose shows a highly significant association with death with a functioning graft caused by cardiovascular disease or infection during years 2–5 after kidney transplantation, even in patients with good graft outcomes in whom steroid treatment would appear to be unnecessary.

The exquisitely sensitive single antigen bead (SAB) technique was shown to detect human leukocyte antigen (HLA) antibodies in sera of healthy male blood donors. Such false reactions can have an impact on critical decisions, especially with respect to the determination of unacceptable HLA-antigen mismatches in patients awaiting a kidney transplant. We tested pretransplant sera of 534 patients on the kidney waiting list using complement-dependent cytotoxicity (CDC), enzyme-linked immunosorbent assay (ELISA) and SAB in parallel. Evidence of HLA antibodies was obtained in 5% of patients using CDC, 14% using ELISA, and 81% using SAB. Among patients without history of an immunizing event, 77% showed evidence of HLA antibodies in SAB. In contrast 98% of these patients were negative in ELISA and CDC. In patients without an immunizing event, SAB-detected antibodies reacted not always weakly but with mean fluorescence intensity (MFI) values as high as 14 440. High-MFI-value antibodies were found in some of these patients with HLA specificities that are rather common in general population, consideration of which would lead to unjustified exclusion of potential kidney donors. False SAB reactions can be unveiled by testing with additional antibody assays. Denial of donor kidneys to recipients based on HLA-antibody specificities detected exclusively in the SAB assay is not advisable.

Natural killer (NK) cell function can be modulated by the killer cell immunoglobulin‐like receptors (KIR) which interact with human leukocyte antigen (HLA) class I molecules on target cells. KIR‐ligand mismatching has recently been shown by van Bergen et al. (American Journal of Transplantation 2011; 11(9): 1959–1964) to be a significant risk factor for long‐term graft loss in HLA‐A, ‐B and ‐DR compatible kidney transplants. To verify this potentially important finding, we performed genotyping of 608 deceased‐donor kidney graft recipients and their HLA‐A, ‐B and ‐DR compatible donors for KIR and HLA, using samples and clinical data provided by the Collaborative Transplant Study. Graft survival of KIR‐ligand‐matched and ‐mismatched transplants was compared. We found no impact of KIR‐ligand mismatching on 10‐year graft survival in HLA‐A, ‐B, ‐DR compatible kidney transplants. Further analysis did not reveal a significant effect of recipient activating/inhibitory KIR or KIR genotypes on graft survival. Our data do not support the concept that KIR‐HLA matching might serve as a tool to improve long‐term renal allograft survival.

Natural killer (NK) cell function can be modulated by the killer cell immunoglobulin-like receptors (KIR) which interact with human leukocyte antigen (HLA) class I molecules on target cells. KIR-ligand mismatching has recently been shown by van Bergen et al. (American Journal of Transplantation 2011; 11(9): 1959–1964) to be a significant risk factor for long-term graft loss in HLA-A, -B and -DR compatible kidney transplants. To verify this potentially important finding, we performed genotyping of 608 deceased-donor kidney graft recipients and their HLA-A, -B and -DR compatible donors for KIR and HLA, using samples and clinical data provided by the Collaborative Transplant Study. Graft survival of KIR-ligand-matched and -mismatched transplants was compared. We found no impact of KIR-ligand mismatching on 10-year graft survival in HLA-A, -B, -DR compatible kidney transplants. Further analysis did not reveal a significant effect of recipient activating/inhibitory KIR or KIR genotypes on graft survival. Our data do not support the concept that KIR-HLA matching might serve as a tool to improve long-term renal allograft survival.

HLA mismatches may correlate with risk of death with a functioning graft (DWFG) because of requirement for higher immunosuppression doses and more antirejection therapy. Deceased‐donor kidney transplants (n = 177 584) performed 1990–2009 and reported to the Collaborative Transplant Study were analyzed. The incidence of DWFG was found to be 4.8% during year 1 posttransplant and 7.7% during years 2–5 (Kaplan–Meier estimates). Most frequent causes of DWFG were infection, cardiovascular disease and malignancy (32.2%, 30.9% and 3.6% in year 1; 16.4%, 29.6% and 15.9% in years 2–5). HLA‐A + B + DR mismatches were significantly associated with DWFG during year 1 (p < 0.001), a correlation that diminished but persisted during years 2–5 (p < 0.001). HLA mismatch was associated with DWFG because of infection (p < 0.001 during year 1, p = 0.043 during years 2–5) or cardiovascular disease (p < 0.001 during year 1, p = 0.030 during years 2–5) but not malignancy. There was also a significant association between HLA mismatch and hospitalization for viral (p < 0.001) or bacterial (p = 0.002) infection. Multivariable analysis showed that mismatches for HLA class II were more strongly associated with both hospitalization and DWFG than mismatches for HLA class I.

HLA mismatches may correlate with risk of death with a functioning graft (DWFG) because of requirement for higher immunosuppression doses and more antirejection therapy. Deceased-donor kidney transplants (n = 177 584) performed 1990–2009 and reported to the Collaborative Transplant Study were analyzed. The incidence of DWFG was found to be 4.8% during year 1 posttransplant and 7.7% during years 2–5 (Kaplan–Meier estimates). Most frequent causes of DWFG were infection, cardiovascular disease and malignancy (32.2%, 30.9% and 3.6% in year 1; 16.4%, 29.6% and 15.9% in years 2–5). HLA-A + B + DR mismatches were significantly associated with DWFG during year 1 (p < 0.001), a correlation that diminished but persisted during years 2–5 (p < 0.001). HLA mismatch was associated with DWFG because of infection (p < 0.001 during year 1, p = 0.043 during years 2–5) or cardiovascular disease (p < 0.001 during year 1, p = 0.030 during years 2–5) but not malignancy. There was also a significant association between HLA mismatch and hospitalization for viral (p < 0.001) or bacterial (p = 0.002) infection. Multivariable analysis showed that mismatches for HLA class II were more strongly associated with both hospitalization and DWFG than mismatches for HLA class I.

Whether treatment with angiotensin‐converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) increases the risk of cancer is controversial. Collaborative transplant study data were analyzed according to whether kidney transplant recipients were treated with ACEi/ARB at year 1. Twenty‐four thousand and ninety patients were studied of whom 9079 (38%) patients received ACEi/ARB. There were 872 nonskin malignancies during years 2–8 posttransplant, including 107 respiratory/intrathoracic tumors. The standardized incidence ratio (SIR) for all nonskin malignancies was similar between the ACEi/ARB (1.91) and no ACEi/ARB (1.81) groups (p = 0.42). For respiratory/intrathoracic tumors, however, SIR was significantly higher with ACEi/ARB (1.65 vs. 1.09 for no ACEi/ARB, p = 0.033). Multivariate Cox regression analysis showed that ACEi/ARB treatment was not associated with an increased risk of respiratory/intrathoracic tumors in nonsmokers. In patients with a history of smoking, however, the risk of respiratory/intrathoracic tumors was 2.77 (95% CI 1.19–6.43, p = 0.018) in patients without ACEi/ARB treatment as compared to 7.10 (95% CI 3.27–15.4, p < 0.001) in patients treated with ACEi/ARB. Our data indicate that in kidney transplant recipients, ACEi/ARB treatment is associated with a significant increase in the rate of respiratory/intrathoracic tumors in the subpopulation of patients with a history of smoking.

Whether treatment with angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) increases the risk of cancer is controversial. Collaborative transplant study data were analyzed according to whether kidney transplant recipients were treated with ACEi/ARB at year 1. Twenty-four thousand and ninety patients were studied of whom 9079 (38%) patients received ACEi/ARB. There were 872 nonskin malignancies during years 2–8 posttransplant, including 107 respiratory/intrathoracic tumors. The standardized incidence ratio (SIR) for all nonskin malignancies was similar between the ACEi/ARB (1.91) and no ACEi/ARB (1.81) groups (p = 0.42). For respiratory/intrathoracic tumors, however, SIR was significantly higher with ACEi/ARB (1.65 vs. 1.09 for no ACEi/ARB, p = 0.033). Multivariate Cox regression analysis showed that ACEi/ARB treatment was not associated with an increased risk of respiratory/intrathoracic tumors in nonsmokers. In patients with a history of smoking, however, the risk of respiratory/intrathoracic tumors was 2.77 (95% CI 1.19–6.43, p = 0.018) in patients without ACEi/ARB treatment as compared to 7.10 (95% CI 3.27–15.4, p < 0.001) in patients treated with ACEi/ARB. Our data indicate that in kidney transplant recipients, ACEi/ARB treatment is associated with a significant increase in the rate of respiratory/intrathoracic tumors in the subpopulation of patients with a history of smoking.

HLA-C is the major inhibitory ligand for killer immunoglobulin-like receptors (KIRs) that are expressed on natural killer (NK) cells. Based on their KIR specificity, HLA-C alleles can be divided into two groups, termed HLA-C1 and HLA-C2. Donor HLA-C group has recently been identified by Hanvesakul et al. (Am J Transplant 2008) as a critical determinant of clinical outcome following liver transplantation: Possession of at least one HLA-C group 2 allele by the donor was associated with significantly improved long-term graft and patient survival, presumably due to an inhibition of host NK cell function. To verify this study, we performed genotyping of 913 deceased liver donors for the relevant KIR epitopes of HLA-C and correlated the presence or absence of donor HLA-C2 genotype with graft and patient survival. In our study, donor HLA-C2 genotype had no impact on 10-year graft or patient survival. We cannot confirm a major role of donor HLA-C2 genotype on long-term allograft survival after liver transplantation.

Der Einfluß des HLA-Systems auf die Erfolgsrate von Nierentransplantationen wurde in einer weltweiten Studie ausgewertet. Der Einfluß der HLA-Chromosomen auf Transplantationen von Verwandtenspendern wurde bestätigt. Bei Transplanta-tionen von Leichenspendern wurde ein hochsignifikanter Effekt der Kompatibilität zwischen Spender und Empfänger für die HLA-A-, -B- und -DR-Antigene festge-stellt (p < 0,0001). Die große Bedeutung einer guten Typisierungsqualitätwurde verdeutlicht durch a) einen signifikanten Einfluß der HLA-A-, -B-Antigene, wenn die Typisierung auf «Split»-Untergruppen durchgeführt wurde, nicht jedoch wenn lediglich «breite» Antigene typisiert wurden, und b) einen verbesserten Effekt der HLA-DR-Kompatibilität, wenn serologische Typisierungsfehler mittels einer molekularbiologischen Typisierung korrigiert wurden. Durch eine Nierenzuteilung nach der HLA-Kompatibilität ist ein Gewinn von 800 Nierenfunktionsjahren je 1000 Transplantationen über einen 10-Jahres-Zeitraum erreichbar.

In hematopoietic stem cell transplantation (HSCT), disparities between recipients and donors for minor histocompatibility antigens (mHags) have been shown to be related to graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. We investigated the effect of mHag mismatches on kidney allograft survival. Out of 33 785 kidney transplants on which DNA and clinical data were available to the Collaborative Transplant Study (CTS), 702 recipientdonor pairs could be identified as HLA-A, -B and -DRB1 matched first transplants of Caucasian origin. These pairs were typed for genetic polymorphisms of the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 and UGT2B17. Because mHags are presented in an HLA-restricted manner, only HLA-A02 positive pairs were included in the analysis of HA-1, HA-2 and HA-8. Similarly, only HLA-A01, HLA-B44 and HLA-A24 positive pairs were considered for the evaluation of HA-3, HB-1 and ACC-1, respectively, whereas UGT2B17 compatible transplants were assessed in HLA-A29 and HLA-B44 positive pairs. None of the mHag disparities showed a statistically significant effect on death-censored 5-year graft survival. This report represents the first large-scale study on the relevance of mHags in kidney transplantation.

In hematopoietic stem cell transplantation (HSCT), disparities between recipients and donors for minor histocompatibility antigens (mHags) have been shown to be related to graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. We investigated the effect of mHag mismatches on kidney allograft survival. Out of 33 785 kidney transplants on which DNA and clinical data were available to the Collaborative Transplant Study (CTS), 702 recipient/donor pairs could be identified as HLA-A, -B and -DRB1 matched first transplants of Caucasian origin. These pairs were typed for genetic polymorphisms of the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 and UGT2B17. Because mHags are presented in an HLA-restricted manner, only HLA-A*02 positive pairs were included in the analysis of HA-1, HA-2 and HA-8. Similarly, only HLA-A*01, HLA-B*44 and HLA-A*24 positive pairs were considered for the evaluation of HA-3, HB-1 and ACC-1, respectively, whereas UGT2B17 compatible transplants were assessed in HLA-A*29 and HLA-B*44 positive pairs. None of the mHag disparities showed a statistically significant effect on death-censored 5-year graft survival. This report represents the first large-scale study on the relevance of mHags in kidney transplantation.

HLA and immunology laboratories are an integral part of clinical kidney transplant programs. They assist transplant clinicians with evaluating the immunological suitability of potential recipients for transplantation and selecting donor-recipient combinations with a low risk of immunological failure. With sophisticated new techniques becoming available for posttransplant immunological monitoring, laboratories play an increasing supporting role during posttransplant follow up. The level of precision at which immunological testing predicts clinical outcome, however, leaves room for improvement. In this article, we summarize the current state of diagnostics, discuss problems, and point out promising developments.

HLA and immunology laboratories are an integral part of clinical kidney transplant programs. They assist transplant clinicians with evaluating the immunological suitability of potential recipients for transplantation and selecting donor-recipient combinations with a low risk of immunological failure. With sophisticated new techniques becoming available for posttransplant immunological monitoring, laboratories play an increasing supporting role during posttransplant follow up. The level of precision at which immunological testing predicts clinical outcome, however, leaves room for improvement. In this article, we summarize the current state of diagnostics, discuss problems, and point out promising developments.

Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We assessed serum soluble CD30 (sCD30) together with in vitro Th2-type responses (IL-4, IL-10, CD4 helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2-year follow-up. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejections did not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p = 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p = 0.005 at 2 years). Tacr versus CsA treatment proved to be an independent variable associated with downregulation of 1-year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01, respectively; logistic regression). Importantly, increased 1-year sCD30 and Neo/CR were associated with decreased glomerular filtration rate at 2 years (p = 0.02 and p < 0.0005, respectively) and evidence of CAN (p < 0.0005). High 1-year sCD30 could not be attributed to enhanced Th2-type responses and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and might be of advantage in patients with elevated sCD30 or neopterin.

Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We assessed serum soluble CD30 (sCD30) together with in vitro Th2-type responses (IL-4, IL-10, CD4 helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2-year follow-up. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejections did not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p = 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p = 0.005 at 2 years). Tacr versus CsA treatment proved to be an independent variable associated with downregulation of 1-year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01, respectively; logistic regression). Importantly, increased 1-year sCD30 and Neo/CR were associated with decreased glomerular filtration rate at 2 years (p = 0.02 and p < 0.0005, respectively) and evidence of CAN (p < 0.0005). High 1-year sCD30 could not be attributed to enhanced Th2-type responses and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and might be of advantage inpatients with elevated sCD30 or neopterin.

This large prospectively conducted observational cohort study examined the risk of lymphoma and other malignancies with mycophenolate mofetil (MMF) in de novo renal transplant recipients. A total of 6751 patients receiving MMF, and an equal number of matched controls receiving non-MMF-based immunosuppression, were identified from two large registries (Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) and Collaborative Transplant Study (CTS)) and followed for 3 years. The primary endpoint was development of lymphoma. Secondary endpoints included development of any malignancy. There was no evidence of any increased risk of developing lymphoma or malignancy with MMF. The risk of developing lymphoma with MMF compared with the non-MMF cohort was not higher in either the CTS registry (relative risk (95% confidence interval); 0.4 (0.17–0.94)) or the OPTN/UNOS registry (1.04 (0.61–1.78)). In the MMF group, there was a trend toward a lower risk of malignancy in both registries (OPTN/UNOS 0.86 (0.69–1.07); CTS 0.79 (0.61–1.02)) and a significant increase in time to malignancy in the CTS dataset (p < 0.026). This study has demonstrated that MMF is not associated with an increased risk of lymphoma or other malignancies post-renal transplant, and may even be associated with a lower risk in some populations.

This large prospectively conducted observational cohort study examined the risk of lymphoma and other malignancies with mycophenolate mofetil (MMF) in de novorenal transplant recipients. A total of 6751 patients receiving MMF, and an equal number of matched controls receiving non‐MMF‐based immunosuppression, were identified from two large registries (Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) and Collaborative Transplant Study (CTS)) and followed for 3 years. The primary endpoint was development of lymphoma. Secondary endpoints included development of any malignancy. There was no evidence of any increased risk of developing lymphoma or malignancy with MMF. The risk of developing lymphoma with MMF compared with the non‐MMF cohort was not higher in either the CTS registry (relative risk (95% confidence interval); 0.4 (0.17–0.94)) or the OPTN/UNOS registry (1.04 (0.61–1.78)). In the MMF group, there was a trend toward a lower risk of malignancy in both registries (OPTN/UNOS 0.86 (0.69–1.07); CTS 0.79 (0.61–1.02)) and a significant increase in time to malignancy in the CTS dataset (p < 0.026). This study has demonstrated that MMF is not associated with an increased risk of lymphoma or other malignancies post‐renal transplant, and may even be associated with a lower risk in some populations.

Differences in early posttransplant immunologic responses between living donor (LDT) and cadaver donor transplant (CDT) recipients have not been thoroughly studied. This is the first study comparing lymphocyte subpopulations and plasma levels of different cytokines, soluble cytokine receptors, cytokine receptor antagonists, and neopterin during the first 2 posttransplant weeks.

BackgroundPrognostic information is essential for optimal treatment of patients with head and neck cancer. We studied the relationship of class I and class II human leukocyte antigens (HLA) on prognosis in patients with head and neck cancer.

When renal amyloidosis has progressed to end‐stage renal failure, most patients are severely affected by systemic amyloidosis and nephropathy. An alternative to chronic dialysis is renal transplantation. We present a patient with amyloid nephropathy who developed recurrent transplant amyloidosis. Renal transplantation was performed in 1985 with a living related donor. In 1990 the patient developed amyloidosis of the graft with membranous nephropathy and tubular acidosis due to hyporeninemic hypoaldosteronism. Secondary amyloidosis has been reported to involve glandular organs inducing hypothyroidism, hypocortisolism and hypoaldosteronism. Cyclosporine has been reported to induce hyporeninemic hypoaldosteronism and tubular acidosis, but not hypocortisolism and hypothyroidism. Progression of the amyloidosis of the graft was confirmed by a renal biopsy in 1993. Data published in the literature indicate that the survival rate of amyloidotic graft recipients is worse than those of non‐amyloidotic graft recipients. This was confirmed in an analysis of the current CTS data which showed an impaired survival rate at 5‐yr of 66+4% (± SE) for patients with amyloidosis (n = 413) as compared with 86 ± 1% (p<0.0001) for patients with glomerulonephritis and 84±1 (p <0.01) for patients with polycystic kidney disease. Graft survival after 5 years was 55±4% in patients with amyloidosis as compared with 63±1% (p=0.02) in patients with glomerulonephritis and 68±1% in patients with polycystic kidney disease. Graft survival was improved in amyloidotic patients treated with cylosporine as compared with patients on steroids and azathioprine (554% vs. 38±8%, p <0.05). It is concluded that renal transplantation is the renal replacement therapy of choice for patients with AA‐type amyloidosis although the overall patient survival is impaired in comparison with patients with other discases.

We examined the pretransplant sera of 154 cadaver kidney recipients for anti‐donor antibodies against T lymphocytes using the flow cytometry technique. All patients had negative routine lymphocytotoxic crossmatches. 31 of the 154 (20%) patients were positive in the flow cytometric T‐cell crossmatch (FACS‐T‐XM). A positive FACS‐T‐XM was associated with irreversible rejection (p < 0.01 at 14 days, p < 0.001 at 30 d, p < 0.001 at 1 year). The 1‐yr graft survival rate of FACS‐T‐XM‐negative patients was 85% in contrast to 58% for FACS‐T‐XM‐positive patients (p < 0.001). 84% of the irreversible rejections in FACS‐T‐XM‐positive patients occurred within the 1st month after transplantation. These results suggest that a positive FACS‐T‐XM should be considered a contraindication for transplantation. We developed a flow cytometric assay to determine the complement‐fixing capacity of antibodies causing a positive FACS‐T‐XM. Of 14 patients who were examined, 10 had noncomplement‐fixing and 4 complement‐fixing antibodies. All 10 patients with noncomplement‐fixing antibodies experienced acute rejections, which were irreversible in 4. These results demonstrate that noncomplement‐fixing anti‐T cell antibodies, which cannot be detected in the lymphocytotoxic crossmatch assay, are clinically relevant.

There is evidence for differences in B‐cell regulation between renal allograft recipients with long‐term stable graft function (ST patients) and patients undergoing chronic rejection (CR patients). To assess the role of T cells in B‐cell regulation, we tested T‐lymphocyte helper and suppressor functions in 26 ST patients (> 1 year posttransplant) and in 13 CR patients. 34 healthy blood donors served as controls. CD4‐positive or CD8‐positive T lymphocytes were cocultured with B lymphocytes and pokeweed mitogen for 6 days. B‐cell differentiation was assessed in a reverse hemolytic plaque assay and by ELISA determination of IgM and IgG in culture supernatants. We found a diminished T helper function and elevated T suppressor activity in ST patients (immunoglobulin‐secreting cell formation, p < 0.001; IgM secretion, p < 0.002; IgG secretion, p < 0.05) but not in CR patients. Elevated counts of CD4 cells with suppressor activity were responsible for the increased T suppression in ST patients. The percentage of CD45R‐positive CD4 cells (suppressorinducer cells) was unchanged in both ST and CR patients. Whereas all CR patients had T helper function in the normal range, 11 of 26 (42%) ST patients had defective T helper activity (p < 0.005). 62% of the ST patients demonstrated T‐cell suppression of immunoglobulin‐secreting cell formation in contrast to 23% of CR patients (p < 0.05). Our data support a role of T suppressor activity in the maintenance of allograft acceptance in long‐term transplant recipients.

Sera of 40 renal transplant recipients were tested for the presence of antiidiotypic antibodies against autologous donor‐reactive recipient T cells. From each patient, a series of cell cultures was established. The cultures were restimulated with specific donor cells for 2 weeks. Cells of each culture were tested in 2‐day MLC assays with the addition of autologous pre‐ or posttransplant serum or 2 control sera. For each patient the proportion of cultures was calculated that was suppressed or stimulated by autologous sera. Stimulation by pretransplant serum was correlated with the number of pretransplant blood transfusions (p<0.01), but not with graft survival. Within 2 months posttransplant, suppressive and stimulating serum factors were induced that correlated significantly with transplant outcome (p < 0.01). Patients with good graft outcome had significantly more cultures that were suppressed by posttransplant serum than patients with rejections. Conversely, stimulation was associated with graft rejection. Our data suggest a posttransplant induction of suppressive and stimulative serum factors that regulate the reactivity of donor‐reactive cell clones.

T-lymphocyte helper and suppressor functions were assessed in 61 hemophilia patients. Twenty one patients were HIV-negative (Group 1), 27 were HIV-positive without having AIDS-related complex (ARC)/AIDS (Group 2), and 13 had ARC/AIDS (Group 3). T, CD4-positive, or CD8- positive T lymphocytes were cocultured with B lymphocytes and pokeweed mitogen for 6 days and immunoglobulin producing cells were assessed in a reverse hemolytic plaque assay. In HIV-infected patients, T cells as well as the CD4-positive T cell subset exhibited reduced helper (P less than .01, Group 2; P less than .0005, Group 3) and elevated suppressor activity (P less than .02, Group 2; P less than .005, Group 3), whereas no significant difference was found between HIV-negative patients and controls. The number of CD4-positive cells was not correlated with CD4 cell function. CD4-positive cells showed no helper activity (less than 10% of control T cells) in 8/11 (73%), but an excessive suppressor activity (greater than 80% suppression of plaque formation) in 6/11 (55%) Group 3 patients. Our results show that defective helper and elevated suppressor functions of T cells in HIV-infected patients are caused not only by a change in the CD4/CD8 cell counts but also by functional abnormalities of the CD4-positive T-cell subset. These abnormal helper and suppressor functions may play a role in the development of the immunodeficiency state of AIDS patients.

The development of lymphocytotoxic antibodies was studied in dialysis patients in relation to the number of blood transfusions they had received. About one-half of the patients did not develop cytotoxins in spite of 30 blood transfusions. cytotoxins were often transient, and sometimes even disappeared in spite of repeated transfusions. Anti-HL-A2 was the most commonly found antibody; however, only 34 of HL-A2-negative patients developed cytotoxins when challenged with blood transfusions. The antigens of the second HL-Alocus do not elicit a greater cytotoxic antibody response than antigens of the first locus.

The contribution of autoimmune phenomena to the pathogenesis of acquired immunodeficiency syndrome (AIDS) is poorly understood. We investigated the relationship between IgG-anti-Fab gamma autoantibodies and the main immunologic feature of AIDS, the decrease of CD4+ helper lymphocytes. Sera of 33 human immunodeficiency virus (HIV) infected (HIV+) hemophilia patients with AIDS/AIDS-related complex (ARC), 57 HIV+ patients without AIDS/ARC, 23 HIV-negative (HIV-) patients, and 76 healthy controls were tested for antibody activity against the Fab region of IgG. Patients with AIDS/ARC had significantly higher IgG-anti- Fab gamma activity than HIV+ patients without AIDS/ARC, HIV- patients, or controls (P less than .0001). A striking inverse association was found between IgG-anti-Fab gamma and CD4+ cell counts (r = -.69; P less than 10(-6)). Sequential testing in 16 AIDS/ARC patients showed that an increase in the IgG-anti-Fab gamma activity was invariably accompanied by a decrease in the CD4+ cell count. IgG-anti-Fab gamma antibodies may play an important role in the immunopathogenesis of AIDS.

Patients with malignant tumors of the head and neck often have immune defects. Higher serum immunoglobulin (Ig)A levels were reported in this group of patients. We investigated whether IgA-anti-Fab- or IgA-anti-F(ab')2autoantibodies, which have been shown to correlate with severe dysfunction of the immune system, also appear in patients with head and neck cancer. Sera of 110 patients with squamous cell carcinoma (SCCHN), eight patients with adenoid cystic carcinoma, and 57 healthy control subjects were tested by enzyme-linked immunosorbent assay for IgA-anti-Fab autoantibody activity. Patients with head and neck cancer showed a higher IgA-anti-Fab activity (optical density (OD) = 399; n= 118) than did healthy control subjects (OD = 84; n= 57; p< 0.0001). An association between stage of disease and IgA-anti-Fab activity could be established in patients with SCCHN. Patients with stage IV disease had a significantly higher IgA-anti-Fab activity (OD = 538; n= 51) than had patients with stage I disease (OD = 283; n= 18; p< 0.05). Patients with stage II (OD = 293; n= 13) or stage III (OD = 379; n= 28) disease had intermediate activity. Also a higher IgA-anti-Fab activity than in healthy control subjects could be shown in the eight patients with adenoid cystic carcinoma (OD = 314; n= 8; p< 0.01). The highest IgA-anti-Fab activity was observed in eight patients with SCCHN who died within 6 months after testing (OD = 1004; n= 8), suggesting an association between autoimmunity and final desintegration of physiologic body functions. The occurrence of IgA-anti-Fab/IgA-anti-F(ab')2autoantibodies might be interpreted as an aspect of immune deficiency in patients with malignant tumors of the head and neck.

Summary The hepatitis C-virus (HCV) is the main etiologic agent of posttransfusion hepatitis (PTH). Most patients depending on hemodialysis need transfusion of blood before kidney transplantation. Of 272 patients after kidney transplantation, 27 (10%) were found to be anti-HCV-ELISA-positive (HCV-Antibody-ELISA, Ortho Diagnostics). The antibodies could be neutralized by HCV C-100-3 antigen. Eight of 22 patients (36%) who had more than one kidney transplantation were classified anti-HCV positive [30% (8/27) of all anti-HCV positive patients]. The number of transfused blood units ranged from 0 to 99 BU. Receiving more than one kidney graft or the transfusion of more than 5 units of blood increased the risk for HCV infection 3.5 or 4.1 times, respectively, compared with one transplantation or less than 5 units of blood. No significant interactions were seen between these two variables. Of the anti-HCV positive patients, 48% were anti-HBc negative as well as HBs-antigen negative, 52% were anti-HBc positive.

If bone marrow transplantation is to become widely applicable in the treatment of patients with leukemia and aplastic anemia, the necessity to have a perfectly histocompatible donor must be overcome. In an effort to define the roles of HL-A type and mixed lymphocyte culture (MLC) reactivity in the determination of successful engraftment and the occurrence of graftversus-host disease (GVHD), we have attempted transplantation of a child with acute myeloblastic leukemia (AML) using an HL-A identical, MLC-reactive sibling donor. Successful engraftment has been accomplished, as documented by the appearance of multiple donor genetic markers in the recipient. There is no evidence of severe GVHD. The recipient is alive, without evidence of leukemia, and has returned to full activities 9 mo after transplantation. The recipient now produces lymphocytes, which have the MLC reactivity that characterize the donor's lymphocytes, rather than that of her own pretransplant lymphocytes. This experience demonstrates that successful bone marrow transplantation in patients with leukemia can be accomplished in the face of MLC reactivity.

To investigate whether autoantibodies against CD4-positive lymphocytes might induce helper dysfunction, autoantibody formation and T-cell function was examined simultaneously in 61 hemophilia patients. Twenty patients were human immunodeficiency virus (HIV)-negative, 26 HIV- positive stage CDC II or III, and 15 were HIV-positive stage CDC IV. T lymphocytes, CD4-positive, or CD8-positive T subsets were cocultured with B lymphocytes and pokeweed mitogen (PWM) for 6 days and Ig- secreting cells were assessed in a reverse hemolytic plaque assay. The presence of IgM, IgG, C3d, or gp120 on the surface of T cells or T subsets was analyzed by flow cytometry. Autoantibodies against CD4- positive T cells were not detected in controls or HIV-negative patients, but were common in HIV-positive patients (20 of 41 patients). In patients with autoantibodies we found an increased incidence of CD4 helper defects (P less than .0001 in CDC II or III patients; P less than .02 in CDC IV patients). 12 of 13 patients with IgM autoantibodies and 4 of 4 with IgG autoantibodies showed CD4 helper defects. Complement fixation had no relevance. Autoantibody formation against CD4 cells was not due to increased in vivo B-cell stimulation (spontaneous plaque formation: 611 +/- 204 PFC/10(6) B cells in autoantibody-negative patients v 650 +/- 202 PFC/10(6) B cells in autoantibody-positive patients; not significant). Thus, our results suggest that autoantibody formation is not caused by a general state of in vivo B-cell activation. Rather, the production of autoantibodies appears to coincide with defects in B-cell proliferation or differentiation, as shown by reduced mitogen-stimulated B-cell responses in CDC II and III patients (P less than .05). Autoantibodies against CD4 cells appear to be involved in the pathogenesis of CD4 helper defects of HIV-infected patients.

Previous reports provided evidence of an immunosuppressive role of natural anti-F(ab′)2antibodies. If suppressive anti-F(ab′)2antibodies also regulated the autoantibody production in cold agglutination, one would expect high titers of anti-F(ab′)2to be associated with low titers of cold agglutinins. Indeed, our previous studies revealed an inverse correlation between IgG-anti-F(ab′)2and cold agglutinins. Many previous experiments focused on anti-F(ab′)2of an antiidiotypic nature. Recent epitope mapping showed that anti-F(ab′)2of healthy persons is not an antiidiotype but recognizes a hinge region sequence. We attempted to answer the question whether this IgG-antihinge antibody is responsible for the previously described association between anti-F(ab′)2and cold agglutinins. IgG-antihinge and IgG-anti-F(ab′)2antibody was determined and statistically analyzed in the serum of 334 patients with cold agglutination. Our experiments revealed a strong correlation between the concentrations of antihinge and the previously described anti-F(ab′)2antibody. The anti-F(ab′)2activity was competitively inhibited by a synthetic hinge peptide. Moreover, patients with high antihinge titers had low cold agglutinin titers, and vice versa. A stratification according to cold agglutinin specificity and disease etiology showed that the inverse correlation is present only in anti-I and anti-i patients suffering from monoclonal B-lymphocyte proliferation. In conclusion, our results confirm the correlation previously described for anti-F(ab′)2antibody and antierythrocyte autoantibody and define for the first time an association between an idiotype-independent anti-IgG autoantibody and cold agglutinin.

In spite of premature claims that the influence of immunological factors on transplant outcome had been eliminated with the introduction of cyclosporine, there is now ample evidence that immunological risk factors continue to play an important role, even with modern immunosuppression. Recent data from the worldwide Collaborative Transplant Study are provided to illustrate the continued strong influence of histocompatibility matching and presensitization as well as the decreased influence of pretransplant blood transfusions on transplant results.

Historical HLA class II serological typing results of transplantations performed in “The Leuven Collaborative Group for Transplantation” were subjected to retrospective Restriction Fragment Length Polymorfism (RFLP) DNA control typing by the Collaborative Transplant Study (CTS) DNA project using Polymerase Chain Reaction (PCR)-based DNA methods. We re-evaluated the serology/RFLP-discrepant CTS DNA data for our local patients transplanted during a historical period (January 1988 until May 1992) before any class II DNA typing was performed in our tissue typing laboratory. These retyping results confirm both the CTS data for patient typing and the Eurotransplant data for donor typing. A confirmed high discrepancy rate of 19.0% (after exclusion of 2.2% transcription error) was found in the patient population. A low discrepancy rate of 6.8% (after exclusion of 2.2% transcription errors) for the donor population is concordant with the Eurotransplant donor data. Only 4 of the 588 individuals were found to be incorrectly typed by the RFLP method; all involving the specificities