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PubMed1987

Comparison of antigen specificity, class II major histocompatibility complex restriction, and in vivo behavior of myelin basic protein-specific T cell lines and clones derived from (BALB/c x SJL/J) mice.

Immunization with myelin basic protein (BP) causes experimental allergic encephalomyelitis (EAE) in certain strains of mice. SJL/J (H-2s) is the prototype sensitive strain. Although BALB/c (H-2d) is resistant to EAE through use of an identical immunization protocol, (BALB/c x SJL/J)F1 hybrid mice develop EAE after immunization with BP. T cell clones specific for BP have been isolated from a highly encephalitogenic line of (BALB/c x SJL/J)F1 hybrid T cells raised against bovine BP. The clones were examined for their H-2 restriction and specificity for heterologous forms of BP (mouse, rat, and bovine BP). The results revealed the clones cross-reacting with mouse (self) BP were almost always restricted to F1 hybrid class II major histocompatibility complex (MHC) elements. In contrast, mouse cross-reactive clones derived from a nonencephalitogenic (BALB/c x SJL/J) T cell line raised against rat BP were largely restricted to H-2d elements. These clones did not cross-react with bovine BP. Four additional lines were generated by carrying the original rat and bovine F1 T cell lines on parental antigen-presenting cells thus generating lines biased toward homozygous (SJL/J, H-2s, or BALB/c, H-2d) restriction elements. These "parentally restricted" T cell lines did not induce EAE when injected in vivo. These results suggest that in this F1 strain sensitivity to T cell-induced EAE is associated with epitopes on murine BP that associate with F1 class II MHC restricting elements. In contrast, nonencephalitogenic T cell lines contain a high proportion of murine cross-reactive clones restricted to H-2d, the haplotype of the classically resistant BALB/c mouse. This work illustrates the use of T cell lines and clones in a model system to further analyze the role of MHC restriction elements in autoimmune disease occurring in heterozygous individuals.

Animals↗

PubMed1988

Cytotoxic T lymphocyte response to minor H-43a alloantigen in H-43b mice. Privileged H-2Kb restriction to the response is not due to immunodominance or epistatic effect but due to Ir gene function of H-2Kb itself.

Previous study demonstrated that anti-H-43a cytotoxic T lymphocyte (CTL) response of H-43b CWB (H-2b) stain carrying non-major histocompatability complex (MHC) genes of C3H and F1 strains raised by crossing CWB with various H-43b strains was restricted exclusively by self H-2Kb (Kb). In the present study, newly produced C3W strain (H-2k, H-43b), which is H-43-congenic to C3H/HeN (H-2k, H-43a), was used as H-43b mice, and possibility of immunodominance of Kb was examined. No anti-H-43a CTL response could be induced in C3W strain and F1 strains raised by crossing C3W with other H-43b strains not carrying Kb. Thus, the possibility of immunodominance of Kb over the other MHC class I alleles could not be supported. We also examined possibility of epistatic effect of I region genes and non-MHC genes on the Kb restriction. (C3W x C57BL/6)F1(I-Ak/b) and (C3W x B6.CH-2bm12)F1(I-Ak/bm12)mice showed equally anti-H-43a CTL response restricted exclusively by self Kb, and (C3W x B10.MBR)F1(Ik/k) mice also showed anti-H-43a CTL response restricted solely by self Kb. Cold target competition experiments demonstrated that H-43b C57BL/10 or A.BY mice, which do not have non-MHC genes of C3H mounted anti-H-43a CTL response restricted solely by self Kb. Thus, no relation of I region genes or non-MHC genes to the Kb restriction was shown. All the results indicate that H-43b mouse strains, including F1, can not achieve anti-H-43a CTL response unless they carry Kb allele. Notably, (C3W x C57BL/6)F1 mice mounted self Kb-restricted anti-H-43a CTL response, whereas (C3W x B6.CH-2bm1)F1 mice carrying mutated Kb could not mount anti-H-43a CTL response at all. These findings indicate strongly that Kb itself is classical Ir gene of anti-H-43a CTL response and directs self Kb restriction of the response.

Animals↗

PubMed1987

Dietary restriction of tyrosine and phenylalanine: inhibition of metastasis of three rodent tumors.

The effects of a combined dietary restriction of tyrosine and phenylalanine on metastasis were investigated with the use of 3 rodent tumor cell lines: B16-bladder 6 (BL6) melanoma inoculated into (C57BL/6 X DBA/2)F1 mice, Lewis lung (3LL) carcinoma inoculated into C57BL/6 mice, and RT7-4bs hepatocarcinoma inoculated into BD-IV rats. When examined for effects on spontaneous metastasis, dietary restriction of tyrosine and phenylalanine had no effect on metastasis to draining lymph nodes in either BL6 or 3LL tumors. However, the restriction did reduce metastasis of RT7-4bs cells to draining lymph nodes by 60%. In all tumor systems, the dietary restriction effectively inhibited the subsequent growth of lymph node tumors. The most marked effect of the dietary restriction was on spontaneous hematogenous metastasis, which was almost totally blocked for BL6 cells and was reduced by 85% for RT7-4bs cells. Tumor-associated splenomegaly also was completely inhibited in 3LL tumor-bearing mice. The selective dietary amino acid restriction failed to reduce initial lung colonization in the experimental metastasis assay but clearly inhibited subsequent tumor outgrowth in the lungs. These findings demonstrate that modification of host nutritional status by restriction of the dietary intake of tyrosine and phenylalanine exerts a dramatic antimetastatic effect directed particularly on spontaneous hematogenous metastasis. Although the preliminary data suggest a primary modulating effect on tumor cell populations growing in diet-restricted animals to reduce inherent metastatic ability, the actual mechanisms remain to be defined.

Animals↗

PubMed1986

What is a 'restrictive' defect?

We studied 211 sets of pulmonary function data to evaluate spirographic findings in patients with restrictive defects, and to determine the significance of the spirographic interpretation of restriction. A combination of clinical and body plethysmographic data was used as the standard for the diagnosis of restriction. Restriction was diagnosed spirographically when forced vital capacity (FVC) was low and the ratio of one-second forced expiratory volume (FEV1) to FVC (FEV1/FVC%) was normal. With these criteria, using 70% as the lower limit of normal for FEV1/FVC%, the spirogram had a 93% sensitivity and an 82% specificity for the detection or exclusion of a restrictive defect. Ten percent of patients with pure obstructive defects by clinical and plethysmographic criteria showed a restrictive defect on the spirogram. Combined obstructive and restrictive defects were rare; in these cases the spirogram showed a restrictive defect but missed the obstructive component.

Asthma↗

PubMed1986

Effects of levels of feed restriction on in vivo and in vitro alterations in drug metabolism and associated enzymes.

The objective of this study was to determine if 15% and 30% feed restriction would enhance drug metabolism similar to that caused by 45% feed restriction. Four groups of weanling male Sprague-Dawley rats were subjected to 0%, 15%, 30%, and 45% feed restriction for 28 days. Feed restriction of 45% significantly enhanced hepatic DNA, microsomal protein, cytochrome P-450, aniline hydroxylase, p-chloromethylaniline-N-demethylase, and decreased hexobarbital sleeping time. The feed restriction of 15% and 30% did not significantly alter the above parameters of drug metabolism. The activities of NADPH-generating enzymes were enhanced by all levels of feed restriction. Thus it is concluded that 15% and 30% feed restriction did not enhance in vivo or in vitro drug metabolism to the extent enhanced by 45% restriction for the same length of time.

Animals↗

PubMed1985

Lyb-5+ B cells can be activated by major histocompatibility complex-restricted as well as unrestricted activation pathways.

It has previously been demonstrated that B cells can be activated through two distinct T helper (Th) cell-dependent pathways, one requiring both carrier-hapten linkage and MHC-restricted T-B interaction and the other requiring neither. In addition, it has been shown that different B cell subpopulations exist and that these subpopulations differ in their activation requirements. Previous studies demonstrated that resting B cells containing an Lyb-5+ subpopulation were activated by MHC-unrestricted T cell signals, whereas resting Lyb-5- B cells were activated only through MHC-restricted T-B interaction. It was suggested that this difference resulted from the ability of Lyb-5+ but not Lyb-5-B cells to respond to soluble MHC-unrestricted Th signals. Because Lyb-5+ B cells were responsive in these previous experiments to MHC-unrestricted Th signals, it could not be determined whether Lyb-5+ B cells were also responsive to MHC-restricted Th signals. Consequently, the present study was undertaken to directly address the question of whether Lyb-5+ B cells can be activated under appropriate conditions by MHC-restricted as well as unrestricted T cell-B cell interactions. It was found that unprimed normal B cells (containing Lyb-5+ and Lyb-5-B cells) but not unprimed xid-defective populations (Lyb-5- only) can be activated by cloned KLH-specific and MHC-restricted Th cells in response to either high or low concentrations of TNP-KLH. The IgM response of Lyb-5+-containing B cells to a high concentration of antigen (10 micrograms/ml) was MHC unrestricted, whereas the IgM response of unprimed Lyb-5+ B cells to a low concentration of antigen (0.001 micrograms/ml) was MHC restricted. Thus, unprimed Lyb-5+ B cells can be activated through both MHC-restricted and unrestricted pathways. It was further demonstrated that the activation requirements of Lyb-5+ and Lyb-5- B cells differed even for MHC-restricted B cell activation.

Animals↗

PubMed1985

Controlling cephalosporin and aminoglycoside costs through pharmacy and therapeutics committee restrictions.

The cost-reducing effect of antibiotic restrictions imposed by a pharmacy and therapeutics (P & T) committee was evaluated. The pharmacy department developed guidelines restricting the use of second-generation cephalosporins and aminoglycosides in cooperation with the infectious disease division. The P & T committee approved the restrictions, and the pharmacy department disseminated information on the program to the hospital's physicians. Specific indications were developed for the use of amikacin, tobramycin, cefoxitin, and cefamandole. In order to prescribe a restricted antibiotic, physicians are required to write an approved indication on the physician's order form. Residents cannot prescribe restricted antibiotics for unapproved indications unless they acquire the signature of an attending physician. Pharmacy personnel closely monitor the restricted antibiotic use and enforce the established guidelines. The major impact of the restrictions was the reversal of a previous trend toward the use of more expensive second-generation cephalosporins and tobramycin to the use of first-generation cephalosporins and gentamicin. Injectable antibiotic expenses decreased by $193,172 in the first 12 months of the program. Antibiotic restrictions imposed by the P & T committee were effective in reducing the cost of antimicrobial therapy.

Aminoglycosides↗

PubMed1979

Influence of controlled dietary restriction on immunologic function and aging.

The underfeeding regimens tested in rodents for life span prolongation and/or immunologic effects result in a complex blend of protein and energy restriction while offering at least adequate amounts of all other essential nutrients. Underfeeding started at weaning and continued throughout life represents the only proved way of slowing the rate of aging in homeotherms. Mounting evidence indicates that underfeeding initiated later in life may also influence life span favorably. Old mice after lifelong restriction, or moderately aged mice (16.5 months) after 4.5 months of restriction, display "younger" immune systems than do age-matched, normally fed controls, as judged by response to mitogens, the mixed lymphocyte reaction, and other determinants. The immunologic effects of underfeeding, when measured quite early in life, are strain-dependent in the mouse. Diets designed to restrict the intake per week of energy (but not protein) produce the same effects on immune response capacity in very young mice as do energy restricted, protein unbalanced regimens. Underfeeding early in life drastically dampens thymic growth and alters the timing of involution. Early restriction also produces a profound lowering of body temperature in young (C57BL/10Sn x C3H/HeDiSn)F1 females. On the other hand, temperature lowering was not observed in males of this hybrid fed normally for the first year of life and restricted for 3 months prior to measurement. The mechanisms behind these various effects of controlled dietary restriction (i.e., undernutrition without malnutrition) are poorly understood at present.

Aging↗

PubMed1982

Influencing drug use through prescribing restrictions.

The effect of several drug restriction policies on benzodiazepine and cephalosporin use was evaluated in a large federal hospital. Computerized drug-use data were examined for the 10-year period from 1972 through 1981. The five major types of drug restrictions implemented were the: (1) requirement that all diazepam prescriptions be countersigned by the chief of staff, (2) deletion of cephalothin sodium from the formulary, (3) required countersignature by a physician from the infectious disease service for all cefazolin sodium prescriptions, (4) requirement that justification accompany all cefazolin sodium prescriptions after the countersignature requirement was lifted, and (5) amendment of the countersignature requirement for diazepam with a series of designated exceptions. All of the restrictions resulted in a decrease in the number of dosage units dispensed; however, the required countersignature by the chief of staff and deletion from the formulary were the most effective in restricting drug use. The effect of the restriction policies appears to be related to the influence or power of the restriction enforcer and the perceived importance of the restriction, as well as the relative difficulty of drug acquisition by the prescriber. Formulary deletion, countersignature requirements, or restricted use to a service or physician are action plans that may alter the use rates of drugs.

Anti-Anxiety Agents↗

PubMed1984

Selection of thymocyte MHC restriction specificity in vitro.

The thymus is critical for the generation of mature T cells with restricted specificity for major histocompatibility complex (MHC) molecules of thymic genotype. The mechanism by which this T cell commitment to self-MHC gene products occurs in vivo prior to the exposure to foreign antigens is unknown. When thymocytes are cocultured with irradiated syngeneic accessory cells, a proliferation of cells specific for self-Class II MHC molecules is observed. This in vitro response is of interest in the context of the physiologic events that occur in the thymus. However, the functional significance of these in vitro proliferating cells, as well as their relationship to antigen-specific, MHC-restricted T cells, has not been defined. Further, whether this in vitro response is capable of influencing the MHC specificity of the thymocytes is unknown. In the work reported here, cells obtained from these cultures were tested for their ability to help a primed B cell antibody response. This approach allowed an analysis of function, antigen and MHC-restriction specificity, and the behavior of these cells upon transfer in vivo. Potent T-helper function was obtained from such cultures for an antigen-dependent, hapten-specific B cell response. When F1 thymocytes were cultured with F1 accessory cells, the T-helper cells recovered could help B cells of both parental MHC haplotypes. However, if the same F1 thymocytes were first cultured with parental accessory cells, they subsequently cooperated only with the corresponding parental or F1 B cells. This MHC restriction was determined by the MHC genotype of the accessory cell in primary culture. Monoclonal antibody blocking studies demonstrated that Ia molecules were critical to this process. Suppression did not account for the observed restrictions. The effector specificity of the T-helper cells could be mapped to the I-A subregion. On adoptive transfer to lethally irradiated hosts, the helper cells could localize to peripheral lymphoid organs. These cells retain their in vitro-imposed restriction specificity even when transferred back to and primed in an F1 environment. Using this experimental protocol, carrier antigen-specific, MHC-restricted priming of these thymic T-helper cells could be detected. These results demonstrate that one can select and amplify functional T-helper cells from cultures of thymocytes whose precise MHC-restriction specificity is determined in vitro.

Animals↗

PubMed1983

Effects of preweaning and postweaning feed restriction on the development of polygenic obese mice.

Polygenic obese (M16) and control (ICR) mice were raised in litters of 8 (N8) or preweaning restricted in litters of 14 (N14). Mice were fed either ad libitum or postweaning restricted by automatic feeders from 4 to 10 weeks of age. All mice were fed ad libitum from 10 to 16 weeks. Preweaning restriction (N14) resulted in mice at 4 weeks with smaller body weights, fat percent, subcutaneous fat depot and adipocyte diameter than N8 mice. Most of the effects of preweaning restriction were overcome by 10 weeks. Obese mice, at 10 and 16 weeks, were heavier and had higher fat percent and larger fat depots with more and larger adipocytes than control mice. Postweaning restriction resulted in mice at 10 weeks with smaller body weight but greater fat percent, especially in the control line. Postweaning restriction of obese mice resulted in a higher percent of fat at 16 weeks. The change in eating pattern, stress or other factors associated with postweaning restriction, as imposed in this study, resulted in an altered metabolism that distributed a greater proportion of energy to fat storage than in the ad libitum fed mice. Ultimate body size and adipose tissue characteristics were determined primarily by genotype, whereas most effects of nutritional restriction were temporary.

Adipose Tissue↗

PubMedDate not supplied

[Actinophage restriction and modification by Streptomyces hygroscopicus and Str. levoris cultures].

The capability for restriction and modification was studied in the cultures of Streptomyces hygroscopicus 0477 and Streptomyces levoris 1331, 2340, 2144 toward the active against them temperate phage and three polyphages. All these cultures were found to be capable of the restriction and modification of the temperate phage. Certain differences in the restriction and modification were established between Str. levoris 1331 and the two other cultures of this species. The culture 1331 could modify the temperate phage only with respect to itself rather than the two other cultures. The phage growing on the culture 1331 was restricted not only by the culture 0477, but also by the strains of Str. levoris 2340 and 2144. At the same time, the phage growing on the strains 2340 and 2144 gave the identical effectiveness of inoculation on any of these cultures, as well as on the culture 1331, and was restricted to the same degree by the culture 0477. One of the examined polyphages 14/3 was not restricted by any of the tested cultures. Two other polyphages SH4 and p4 were restricted only by the culture 2144. However, the modification by this culture was not observed. Among the studied cultures of Str. levoris, the culture 2144 was most capable of the restriction.

Bacteriophages↗

PubMed1995

CTL in mice immunized with human mucin 1 are MHC-restricted.

CTLs that recognize tumor Ags have been described in mice and humans, particularly for melanoma. These CTLs are CD8+, which is MHC-restricted. In contrast, in human carcinomas of the breast, pancreas, or ovary, and in multiple myeloma, CD8+ CTLs have been described that lyse targets expressing human MUC1 in a non-MHC-restricted manner. On the basis of these observations, we immunized mice with conjugates of mannan-human fusion protein, human mucin 1 (MUC1), which produced CD8+ CTLs. In contrast to the human anti-MUC1 CTLs found in cancer patients, the murine anti-MUC1 CTLs were clearly MHC-restricted, e.g., in inbred mice of the H-2-b, d, k, s, or z haplotypes; the H-2 restriction was also confirmed in H-2 congenic strains. Tests of H-2 recombinant strains demonstrated that MUC1 peptides were able to associate with D or K class I molecules of the b, d, or k haplotypes. Mice lacking MHC-class I molecules made weak CTL responses that were H-2Db-restricted, and in the class I H-2Kbm1 mutant strain, CTL restriction was also shown. Finally, cold target inhibition studies demonstrated that Kb and Db are recognized similarly, but Kk is less well recognized. Thus, anti-MUC1 CTLs induced by immunization of mice are different from those obtained from patients. The immunization of cancer patients with MUC1 peptides is now undergoing clinical trials and it will be of interest to observe whether the CTLs induced are HLA-restricted, not restricted, or whether both types of CTLs are produced.

Animals↗

PubMed1994

Metabolic responses to episodes of partial dietary restriction in undernourished Wistar rats.

Wistar rat pups raised in large litters (LL) and small litters (SL) prior to weaning had access to ad libitum dietary intakes up to the age of 90 days. At 90 and again at 180 days they were partially diet restricted for a period of 15 days. Body weights, resting metabolic rates (RMR) and capacity for nonshivering thermogenesis (NST) was evaluated prior to, during and after the period of energy restriction. Responses were compared with 180 day rats from both groups who had been diet restricted for the first time at 180 days. Body weight losses were greater in the latter group. Groups of rats exposed to dietary restriction once, had higher body weights than rats of identical ages who had not been restricted. RMR decreased in all groups during restriction. However, reductions in NST were seen only in nutritionally deprived animals and in well-nourished controls who were partially restricted once. Changes in NST contribute to metabolic efficiency seen during episodic dietary restriction.

Animal Nutritional Physiological Phenomena↗

PubMed1994

Effect of nutritional and environmental restrictions on discrimination learning behaviour of juvenile rats.

Effects of nutritional and environmental restrictions on discrimination learning in a single unit black/white T-maze were studied in albino rats. Nutritional restrictions were imposed by 25 and 50% dietary restriction and environmental restrictions were given for 3 and 6 weeks. Both the restrictions were imposed at 46th day after birth. Long-term (6 weeks) environmental restriction significantly impaired the original and reversal discrimination learning, however, short-term (3 weeks) restriction had no effect. Nutritional (dietary) restrictions, on the other hand, had no effect on both learning performances. Interaction between these two variables was also statistically insignificant.

Animals↗

PubMed1993

A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells.

NK cells and IL-2-propagated splenic T cells mediate non-MHC-restricted cytotoxicity. The molecules involved in this process are not well defined. We describe a novel 66-kDa cell surface molecule called 2B4 that is expressed on cells that mediate non-MHC-restricted cytotoxicity. All resting and rIL-2 cultured NK cells and a significant number of T cells cultured in high doses of rIL-2 are 2B4+. In fresh as well as cultured spleen cells, all non-MHC-restricted cytotoxicity is contained within the 2B4+ population. In addition to defining cells capable of non-MHC-restricted killing, the 2B4 molecule is also involved in modulation of their function. In the presence of anti-2B4, the lytic activity of cultured NK cells and non-MHC-restricted T cells against a wide variety of FcR- and FcR+ targets is greatly augmented. Anti-2B4 is also able to transduce other signals in IL-2-activated NK cells such as IFN-gamma secretion and granule exocytosis. In addition, 2B4+ T cells can specifically lyse the 2B4 hybridoma cells. Unlike many other activation and adhesion molecules (such as murine CD2, LFA-1, and CD16), 2B4 expression is restricted to cells that mediate NK-like killing. Conversely, highly activated T cells that do not express 2B4 do not mediate non-MHC-restricted killing. Together these data suggest that the 2B4 molecule is likely to be a part of a receptor complex or a component of signal-transducing complex on cells that mediate non-MHC-restricted killing.

Animals↗

PubMed1993

HIV-1 envelope protein is expressed on the surface of infected cells before its processing and presentation to class II-restricted T lymphocytes.

T lymphocytes are activated upon binding of their Ag receptors to a complex of Ag-derived peptides and MHC class I or class II molecules expressed on the surface of APC. It is now well established that APC degrade exogenous Ag in acidic endosomal compartments, and that Ag fragments bind to class II molecules moving through these compartments on their way to the surface of the APC. Although peptides derived from some endogenous Ag can also bind to class II molecules and subsequently be recognized by class II-restricted T cells, the intracellular trafficking pathways that enable endogenous proteins to be processed for association with class II molecules remain controversial. We have analyzed the mechanism by which the envelope (env) protein of the HIV-1 is processed in infected cells for recognition by class II-restricted T cells. A large number of env-specific class II-restricted human CTL clones were shown to lyse B-lymphoblastoid cell lines expressing the env. A novel dilutional assay proved that A novel dilutional assay proved that recognition of endogenous env protein was not a consequence of release and re-uptake of the env protein and subsequent processing by the standard class II-restricted pathway. Processing of endogenous env protein required that the protein be co-translationally translocated into the endoplasmic reticulum (ER) and then exit the ER, since the class II-restricted CTL did not recognize env protein localized to the cytosol or retained in the ER of target cells. Under these conditions, however, class I-restricted recognition was readily demonstrated. Finally, class II-restricted recognition was strikingly dependent upon the steady state level of surface env protein, since extracellular reagents that removed intact env protein from the surface of target cells inhibited recognition. This inhibition operated at the Ag-processing level rather than at the level of subsequent Ag recognition. These results provide the first direct evidence that endogenously synthesized membrane proteins enter the class II-restricted Ag-processing pathway after expression on the cell surface in an intact form.

Antigen-Presenting Cells↗

PubMed1993

Caloric restriction and intervention in pancreatic carcinogenesis in the rat.

In two experiments, the effects of caloric restriction during the postinitiation phase of pancreatic carcinogenesis were evaluated. Male Lewis rats were given injections of azaserine at 14 days of age and weaned to the postinitiation test protocols at 21 days of age. In the first experiment, the caloric content of the diets was restricted by 10, 15, 20, and 30% of the intakes of the ad libitum-fed rats. A sixth group was fed diet ad libitum for only 5-6 h/day; i.e., they were "meal-fed". The development of putative preneoplastic lesions (henceforth termed foci) was evaluated by quantitative stereological (morphometric) analysis of the pancreas. Caloric restriction during the 4-month postinitiation phase resulted in a significant reduction in focal development beginning at 10% caloric restriction and increasing with more severe restriction. The caloric intake of the meal-fed group closely matched the caloric intake of the 10 or 15% caloric restriction groups and the focal response of the meal-fed rats was similar to the groups restricted in calories by 15 to 20%. In the second experiment, rats were initiated with azaserine and weaned to one of four groups: ad libitum; meal-fed; meal-fed for 2 months and ad libitum thereafter; or ad libitum for 2 months and meal-fed thereafter. Foci were evaluated at 2 and 4 months; neoplasm incidence and multiplicity were determined at 14 months postinitiation. Compared to the ad libitum group, the meal-fed group had significantly fewer foci at all times of evaluation and significantly fewer neoplasms. When rats were meal fed for 2 months and then switched to ad libitum feeding for the remainder of the experiment, the focal outcome at 4 months was similar to the group meal fed for all 4 months; and at 14 months the neoplastic outcome was intermediate between the ad libitum and the meal-fed group. Intervention in the ad libitum feeding regimen at 2 months by meal feeding for the remainder of the experiment resulted in a significant decrease in the focal and neoplastic development, as compared to the group fed ad libitum continuously. These two intervention groups were intermediate in response between the meal-fed and ad libitum-fed groups. These results indicate that the postinitiation phase of pancreatic carcinogenesis can be modulated by relatively simple dietary interventions such as moderate caloric restriction.

Animals↗