Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet ␤ cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged >12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8 ؉ T-cell proportions in islets. Levels of ␤-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after ␤-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of ␤ cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.

Rotaviruses have been implicated as a possible viral trigger for exacerbations in islet autoimmunity, suggesting they might modulate type 1 diabetes development. In this study, the ability of rotavirus strain RRV to infect the pancreas and affect insulitis and diabetes was examined in nonobese diabetic (NOD) mice, an experimental model of type 1 diabetes. Mice were inoculated either orally or intraperitoneally as infants or young adults. In infant mice inoculated orally, rotavirus antigen was detected in pancreatic macrophages outside islets and infectious virus was found in blood cells, pancreas, spleen, and liver. Extraintestinal RRV spread and pancreatic presence of infectious virus also occurred in intraperitoneally inoculated infant and adult mice. The initiation of insulitis was unaltered by infection. The onset of diabetes was delayed in infant mice inoculated orally and infant and adult mice inoculated intraperitoneally. In contrast, adult mice inoculated orally showed no evidence of pancreatic RRV, the lowest rate of detectable RRV replication, and no diabetes modulation. Thus, the ability of RRV infection to modulate diabetes development in infant and young adult NOD mice was related to the overall extent of detectable virus replication and the presence of infectious virus extraintestinally, including in the pancreas. These studies show that RRV infection of infant and young adult NOD mice provides significant protection against diabetes. As these findings do not support the hypothesis that rotavirus triggers autoimmunity related to type 1 diabetes, further research is needed to resolve this issue.

Induction of immune tolerance in patients with severe hemophilia A and inhibitors to factor VIII was attempted by daily infusion of 50 U of factor VIII per kilogram of body weight without adjunctive immunosuppressive drugs. Modest initial anamnestic elevation of inhibitor levels occurred in six patients within the first month of therapy; inhibitor levels then fell sharply. The other six patients had no increase in inhibitor levels while on the study protocol. Inhibitors became undetectable within one to ten months in nine of the patients; they now receive smaller and less frequent infusions of factor VIII to maintain suppression. Inhibitors were not eradicated in three patients, who had the highest baseline and historic inhibitor levels. Ten patients gave consent for human immunodeficiency virus (HIV) testing; three had no antibody to HIV at the outset. Two of these patients seroconverted while on the protocol, one of whom had received only donor-screened, heat-treated factor VIII. Thus, the benefits of inhibitor suppression must be weighed against the risks of HIV seroconversion or transient elevation of inhibitor levels, as well as against the cost of the factor concentrate used.

We studied the characteristics and temporal trends of AIDS- associated non-Hodgkin's lymphoma (AIDS-NHL) in individuals with hemophilia. Prospective data were collected on 33 HIV-positive hemophiliacs with AIDS-NHL enrolled in the Hemophilia Malignancy Study (HMS), of whom 21 had primary and 12 had secondary or subsequent AIDS-defining illnesses, and analyzed for frequency and temporal trends. As compared with primary AIDS- NHL, secondary AIDS-NHL occurred at an older mean age, 37 versus 29 years (p = 0.12); at a lower mean CD4 count, 46 versus 154 (p = 0.07); after a longer period of immunosuppression (CD4 < 200/microl), 41 versus 16 months (p = 0.03); and with shorter median survival, 2 versus 7 months (p = 0.09). The presence of EBV in tumor tissue was associated with shorter survival, 1 versus 7 months (p = 0.17). Between 1981 and 1988 and 1989 and 1994, the proportion of primary AIDS diagnoses that were AIDS-NHL changed minimally, 4.6 versus 6.1%, whereas there were significant decreases in Pneumocystis carinii pneumonia (PCP, p = 0.02) and wasting (p = 0.07), and an increase in Candida (p = 0.004). These findings confirm that an increasing proportion of AIDS-NHL in hemophiliacs are occurring as secondary or later AIDS diagnoses, and they are associated with prolonged duration of immunosuppression.

Factor VIII (FVIII), 50 U/Kg/day, was given without immunosuppressive drugs to 11 patients with hemophilia A and inhibitor. Interval since inhibitor diagnosis was 4-6 years (yr) in 3 cases and 12-27 yr in others. Six had received no FVIII since inhibitor diagnosis. Intervals since last FVIII use were 2 months (mo) in 3 cases and 3-15 yr in others. Historic peak inhibitor levels were 3,8,9,10,25,27,64,375,809,1100 and 2780 Bethesda units (BU). Levels at start of protocol (baseline) were under one BU in 7 cases and 2,42,265 and 398 in others. Evidence of HIV. infection exists in 10 patients: 8 of 9 tested have HIV antibody, 7 of 11 tested have low T4 cell counts and 4 currently have AIDS-related complex. Results after 4-31 mo (median 10) are as follows. Peak inhibitor levels on protocol exceeded baseline in only 6 cases and exceeded historic peaks in only 2 cases. All peaks occurred during the first mo and levels fell markedly by the second. All patients but one had levels below baseline by the third mo. Among 7 patients with one BU or less baseline, no inhibitor was detected after one mo in 4 cases and after 3 mo in 2 cases; another child still has trace inhibitor after 8 mo. A child with baseline 2 BU had no inhibitor after 4 mo. Three older patients have not responded completely. In 2 adults who began the protocol 2 mo after intense FVIII use for hemorrhages, baselines of 275 and 398 BU fell rapidly in the first 4 mo but then plateaued around 20-30 BU despite 9 and 26 mo further therapy. In a teenager who began the protocol 4 yr after intense FVIII use, the baseline of 42 BU has not fallen in 4 mo of therapy. Thus, rapid induction of immune tolerance was achieved in 7 of 8 patients with low baselines; the program was less useful in patients with high baselines. Of 4 patients resistant to full induction of immune tolerance, all have evidence of HIV infection; 3 were tested and have HIV antibody, 2 have low T4 counts and 2 have ARC. Thus, the immune suppression of HIV infection may not potentiate induction of FVIII tolerance. All patients achieving FVIII tolerance remain of FVIII prophylaxis. In some, low-level inhibitors emerged on attempts at withdrawal. Induction of immune tolerance with FVIII is advised for patients with currently-low inhibitor levels because of the high success rate.