The role of endogenous opioids in moderate exercise training-induced enhancement of the secondary antibody response in mice.

BACKGROUND AND PURPOSE: Moderate exercise training (60%-80% of maximal oxygen uptake) enhances the secondary antibody response. The mechanism underlying this enhancement, however, has not been determined. In moderate doses, endogenous opioids such as enkephalins enhance antibody response. Furthermore, serum concentrations of endogenous opioids increase in response to exercise, and training programs augment this effect. Therefore, the enhancement of the secondary antibody response induced by moderate exercise may be brought about, in part, by endogenous opioids. The purpose of this study was to examine the effects of naltrexone (an opioid antagonist) on the enhancement of secondary antibody response induced by moderate exercise in young mice. SUBJECTS AND METHODS: C57BL/6 mice immunized to human serum albumin (HSA) were randomly assigned to 1 of 3 groups: naltrexone, placebo, or control (received no intervention). Then, the mice in each group were randomly assigned to either an exercise group (treadmill running at 15 m/min, 0ø slope, 5 days per week for 8 weeks) or a non-exercise group. At the end of 8 weeks, booster immunization was given, and the mice in the exercise group continued to exercise. Ten days later, when high levels of antibodies are produced in secondary antibody response, anti-HSA antibodies in serum were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: With naltrexone implantation, mice that exercised showed a depression of secondary antibody response as compared with mice that exercised and either received a placebo or did not receive any intervention. DISCUSSION AND CONCLUSION: Endogenous opioids may play a role in the enhancement of the secondary antibody response observed after moderate exercise.

The effects of intense physical exercise on secondary antibody response in young and old mice.

BACKGROUND AND PURPOSE: Based largely on data from young subjects, intense physical exercise is believed to suppress immune function. In addition, immune function, including secondary antibody response, declines with advancing age. Therefore, intense exercise in old subjects may further suppress the secondary antibody response. The purpose of this in vivo study was to investigate the effects of intense physical exercise on secondary antibody response in young (6-8 weeks) and old (22-24 months) C57BL/6 mice. SUBJECTS AND METHODS: Data were obtained from 22 young and 18 old C57BL/6 mice that were immunized to human serum albumin (HSA) and randomly divided into 3 groups. Two groups were exposed to a single bout of intense exercise to exhaustion and immediately boosted with an injection of HSA. The first group did not exercise further, but the second group continued with daily bouts of intense exercise to exhaustion for 9 days. The third group (control group) did not undergo intense exercise, but received the booster injection of HSA at the same time as the other groups. Ten days after the HSA booster injection, when high level of antibodies are produced in secondary antibody response, serum anti-HSA antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: Young mice did not show suppression of secondary antibody response following intense exercise. However, old mice, exposed to a single bout of intense exercise, had an enhanced response similar to the response seen in young control mice. CONCLUSION AND DISCUSSION: The widely accepted hypothesis of immunosuppression resulting from intense exercise may not be true for old mice.

Follicular dendritic cell (FDC) precursors in primary lymphoid tissues.

The origin of follicular dendritic cells (FDC) is unresolved, and as such, remains controversial. Based on the migration of Ag-transporting cells (ATC) into lymphoid follicles and the phenotypic similarity between FDC and ATC, one hypothesis is that ATC may represent emigrating FDC precursors. This contrasts with the view that FDC originate from local stromal cells in the secondary lymphoid tissues. Mice homozygous for the severe combined immunodeficiency (prkdc(scid)) mutation (scid) lack FDC. Thus, they provide a powerful tool for assessing de novo generation of FDC. To test whether FDC precursors could be found in bone marrow or fetal liver, scid/scid mice were reconstituted with either: 1) bone marrow cells from (BALB/c x C57BL/6)F1 donors, 2) bone marrow cells from ROSA BL/6 F1 (lacZ-transfected) mice, 3) rat bone marrow cells, or 4) rat fetal liver cells. Six to eight weeks after reconstitution with F1 bone marrow, cells reactive with the FDC-labeling mAb, FDC-M1, also expressed donor class I molecules on their surfaces. Similarly in mice reconstituted with lacZ-transfected bone marrow cells, these cells were also positive for the lacZ gene product. Furthermore, in spleens of animals reconstituted with either rat bone marrow or rat fetal liver, rat FDC were identified using the specifically labeling mAb, ED5. In all cases, host FDC were also present, indicating that scid/scid mice have FDC precursors that will mature in the presence of allogeneic or xenogeneic lymphoid cells. In summary, FDC can be derived from progenitor cells present in primary lymphoid tissues.

Induction of functional follicular dendritic cell development in severe combined immunodeficiency mice. Influence of B and T cells.

Ag injected into immune mice immediately complexes with specific antibody. Immune complexes not phagocytosed by macrophages are transported by Ag transport cells to lymph node follicles for trapping by follicular dendritic cells (FDC). These FDC serve as a long term repository of unprocessed Ag that is believed to maintain both B cell memory and the secondary antibody response. Severe combined immunodeficiency mice lack functional B cells and T cells. Consequently, this mutation also appears to affect the ability to produce Ag-retaining FDC. to assess B and T cell requirements for FDC development and function, severe combined immunodeficiency mice were reconstituted with BM, or mature B and T cells. The development of a FDC reticulum, a three-dimensional network produced by the intertwining of FDC dendrites was assessed by Ag trapping on FDC using the histochemically detectable Ag horseradish peroxidase and quantitated by morphometry. The results showed that bone marrow transplants or B and T cells transferred together supply the required elements for the development of severe combined immunodeficiency FDC reticula that function in Ag trapping and the induction of the germinal center. In contrast, B cells or T cells injected separately induced a minimal development of FDC reticulum. The B and T cell requirements demonstrated here strongly indicate that B-T cell collaboration and the factors these cells produce are essential for FDC development.

Follicular dendritic cells in the alternative antigen transport pathway: microenvironment, cellular events, age and retrovirus related alterations.

Follicular dendritic cells (FDC) are located in lymphoid follicles of secondary lymphoid tissues and play a pivotal role in the initiation and maintenance of the secondary antibody response. FDC are an integral part of the microenvironment of the follicle and function as members of the 'alternative antigen transport pathway.' This pathway consisting of the antigen transport cell-FDC-ICCOSOME-B cell axis, leads to the formation of germinal centers where antibody-forming cell and memory B cell development are initiated through interaction of FDC-retained antigen, B cells and T helper cells. Evidence suggests that these interactions are down-regulated through antibody feedback, or as needed, reactivated with the utilization of FDC-retained antigen for the maintenance of antibody levels. Age- and retrovirus-related FDC defects seriously compromise the capacity of this pathway to maintain immunity.

Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing.

The present study was initiated to determine if an early phase of germinal centre (GC) development is associated with the generation of antibody-forming cells (AFC). Germinal centres in draining lymph nodes from immune mice were examined histochemically after secondary immunization for the presence of AFC at both the light and electron microscopic levels. Additionally, peanut agglutinin (PNA) high (Hi) GC B cells were isolated, placed in cell culture and specific antibody production was monitored at successive intervals. Electron microscopy showed that plasma cells in all stages of differentiation were present within GC at 3-5 days and to a lesser extent at 7 days following antigenic challenge. Furthermore, PNAHi GC B cells obtained between Days 3 and 5 spontaneously produced specific IgG when placed in culture. Germinal centre B cells isolated either before or after this period did not produce antibody without the addition of T-cell cytokines. Induction of AFC in GC occurred at the time when GC B cells acquire follicular dendritic cell (FDC)-derived, immune complex-coated bodies (iccosomes) and process and present this antigen to helper T cells. This suggested a causal relationship between iccosome release and AFC induction. Support for this was obtained by examination of AFC induction in aged mice where iccosome release has not been observed. Peanut agglutinin-positive GC B cells isolated from aged mice on Days 3-5 after antigen challenge failed to spontaneously produce specific antibody. Collectively, these data show that GC development 3-5 days after booster immunization results in AFC generation and suggests a role for FDC iccosomes in their induction.