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PubMed1990

Dietary restriction augments erythropoiesis in mice.

Previously, we have reported that a 40% dietary restriction caused microcytic and short-lived erythrocytes without anemia in mice (Internat. J. Vitr. Nutr. Res. (1989) 59, 406-412). To elucidate the mechanism of these phenomena, the effects of dietary restriction on the proliferation of erythroid precursor cells were investigated. In the diet restricted mice, a striking increase of erythropoietin (EP - responsive erythroid precursor cells without increment of EP was observed. Remarkable increases in the numbers of femoral nucleated cells and erythroid stem cells (CFU-S) were also observed in the diet restricted mice. Furthermore, the percentage of femoral CFU-S in DNA synthetic stage (S phase) revealed remarkably higher levels in the diet restricted mice than in the control mice. Our results strongly suggest that the microcytic change of erythrocytes in the diet restricted mice may be attributed to the increased number of erythroid precursor cells without an increment of hemoglobin synthesis and that the avoidance of becoming anemic from the short-lived erythrocytes in the diet restricted mice may be caused by a vigorous erythropoiesis.

Anemia↗

PubMed1990

Significant calcium accumulation in fragile erythrocytes by dietary restriction in mice.

Previously we reported that mice adapted to a 40% dietary restriction showed shortened erythrocyte life span (Internat. J. Vit. Nutr. Res. 1989, 59, 406-412). To clarify the mechanism of this phenomenon, influences of dietary restriction on erythrocyte fragility and on some factors associated with erythrocyte deformability were investigated. Forty percent dietary restriction caused an increase of erythrocyte osmotic fragility, a remarkable decrease of ATP levels and a striking accumulation of calcium in erythrocytes. In the diet restricted mice, it was further observed in the erythrocytes that the activity of rate limiting enzymes of glycolysis was significantly decreased. Remarkable decreases of the activities of calmodulin and membrane Ca2+/Mg2(+)-ATPase were also demonstrated in the erythrocytes from the diet restricted mice. These results strongly suggest that the fragile and short-lived erythrocytes in the diet restricted mice may be caused by the decreased activity of pumping out calcium from the cells. The fragile erythrocytes may be destroyed and removed from the blood flow earlier than flexible erythrocytes of the control mice. However, it is also suggested that the essential function of the erythrocytes, the oxygen supply to the peripheral tissues, may be maintained as 2,3-bisphosphoglyceric acid levels were not altered with erythrocyte aging in spite of the decreased glycolytic activity in the diet restricted mice.

Adenosine Triphosphate↗

PubMed1990

[CD4+T cells restricted by DQ not by DR support CD8+T cells to grow].

Much attention has been paid whether there are any differences in regulating the human immune response between HLA-DR and -DQ molecules encoded by the genes within the HLA class II multigene family. Previous studies have suggested that HLA DQ molecules control low responsiveness through activating CD4 T cells which generate CD8 positive T cells, whereas HLA -DR molecules control high responsiveness through activating CD4 helper T cells. To examine this model we investigated the streptococcal cell wall antigen (SCW) specific T cell lines restricted by either DR or DQ molecule. To identify the restricting molecules, L cell transfectants expressing DQw1, DR2AB1 or DR2AB5 from Dw12 haplotype or DQw4, DR4 or DRw53 from DW15 haplotype were used. 1. From individuals with Dw12 which is a low responder haplotype to SCW, T cell clones specific to SCW and restricted by HLA-DQw1 or DR2 were identified, whereas from individuals with Dw15 which is a high responder haplotype, only DR4 or DRw53 restricted T cell clones were identified and DQw4 restricted T cells were never observed. 2. SCW specific CD4 T cells restricted by DQw1 were able to support the growth of CD8 positive cells, whereas those restricted by DR4 could not do so. 3. The CD8 T cells also required autologous antigen presenting cells and SCW to grow, and they completely blocked the immune response to SCW in vitro. These observations clearly demonstrated the distinct function of HLA-DQ and -DR molecules in regulating the human immune response to SCW.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1987

Effect of age and dietary restriction on the expression of alpha 2u-globulin.

The effect of aging on the expression of alpha 2u-globulin was studied in liver tissue from 6-30-month-old male Fischer F344 rats. The synthesis of alpha 2u-globulin by suspensions of isolated hepatocytes decreased 90% between 6 and 22 months of age. The levels of alpha 2u-globulin mRNA and the transcription of alpha 2u-globulin genes by isolated liver nuclei decreased 80-85% between 5 and 24 months of age. Because alpha 2u-globulin has been suggested to be a "senescence marker protein," the expression of alpha 2u-globulin was measured in rats fed a diet restricted in calories. This dietary restriction procedure has been shown to increase significantly the longevity of rodents. The expression of alpha 2u-globulin was compared in liver tissue from 18-month-old rats fed ad libitum and a restricted diet (40% restriction of total calories). The synthesis, mRNA levels, and transcription of alpha 2u-globulin were 1.8-3-fold higher for liver tissue from restricted rats compared to liver tissue from rats fed ad libitum. Therefore, dietary restriction alters the age-related change in the expression of alpha 2u-globulin. Our results demonstrate that the changes in alpha 2u-globulin expression that arise during aging or dietary restriction are regulated at the level of transcription.

Aging↗

PubMed1989

Computerized morphometric quantitation of cellular features in splenocytes from normal and nutrient-restricted mice.

The morphometric analysis of splenocytes reveals quantitative changes in the chromatin and cytoplasm that may be used to distinguish between cells from normally fed animals and cells from subjects fed restricted diets. Analysis of Feulgen-stained and Papanicolaou-stained cells from mice fed normal diets and mice fed either calorie-restricted diets or isocaloric but protein-restricted diets showed an approximately 10% reduction in the nuclear area and in the total optical density (TOD) of stained chromatin in cells from diet-restricted mice. Some changes in chromatin texture features were also observed. Utilization of nuclear area, TOD and one textural feature in a linear discriminant analysis produced a distinct separation of the cells from dietary-restricted mice and the cells from normally fed subjects; this was observed with both Feulgen-stained and Papanicolaou-stained cells. The cellular effect of dietary restriction was more noticeable in the cytoplasm than in the nucleoplasm; Papanicolaou-stained cells from diet-restricted animals showed a 23% reduction in the cytoplasmic TOD and a 10% reduction in the nuclear TOD. This study shows that computerized morphometric analysis may be used in place of or in conjunction with other measurement procedures and chemical tests to quantitate and differentiate cells subjected to different types and levels of nutritional stress.

Animals↗

PubMed1989

Growth of whole body and organs of growing rats during feed restriction and subsequent realimentation.

Fifty-six Sprague-Dawley male rats (average body weight 70.6 +/- SD 11.6 g) were divided into two equal groups. One group was fed a 17% protein (N x 6.25) diet ad libitum for 42 d (Control). The second group was fed the same diet at 60% of the intake of the Control group for 14d (Restricted) and ad libitum for the remaining 28 d. Three rats per group were euthanized on d 1 and five rats per group on d 7, 14, 21, 28, and 42 and weights of the body, heart, spleen, liver, kidneys, epididymal fat, empty stomach, large and small intestines, and length of the left femur were recorded. The empty stomach, large and small intestines were dried to constant weight at 65 degrees C and assayed for crude protein content. Body weight, feed efficiency, weights of the heart, liver and epididymal fat were significantly reduced, while relative weight of the stomach and crude protein content of the small intestine were significantly increased in the restricted group during the period of feed restriction. Body and organ weights, however, compensated and caught up with control values within 14 d of feed rehabilitation and, by 28 d of realimentation, body weight, heart, liver and stomach weights were significantly greater in restricted than in control rats. Femur length was reduced by feed restriction, but continued to increase during restriction and realimentation. Gastrointestinal tract segments were less affected by feed restriction and responded more quickly to realimentation than the whole body.

Animal Feed↗

PubMedDate not supplied

Effect of food restriction on the metabolism of dimethylnitrosamine (NDMA) in rats.

The influence of food restriction on the macromolecular interactions of the hepatocarcinogen dimethylnitrosamine (NDMA) in the livers of male Sprague Dawley rats was investigated. Two-three month old rats were food restricted (FR) (40% with respect to ad libitum fed rats) for three weeks. The liver weight, total protein, microsomal and cytoplasmic protein, cytochrome P-450 and DNA content per whole liver were all reduced significantly in food restricted rats. Five hours after a single dose of (14C) NDMA (28 mg/k.b.w., 21 microCi/rat) the levels of 7-methylguanine increased in restricted rats by 32%. Cytochrome P-450 mediated generation of HCHO from NDMA (1.8 fold) in restricted rats was greater. Binding of NDMA derived radioactivity to total hepatic proteins decreased by 46% in restricted rats. These results suggest that food restriction enhances the metabolic activation of dimethylnitrosamine in Sprague Dawley rats.

Animals↗

PubMed1988

Intrinsic resistance to viral infection. Mouse macrophage restriction of herpes simplex virus replication.

Macrophages isolated from mice resistant to acute (lethal) infection with a neurovirulent isolate of HSV-1 express intrinsic resistance to viral infection in vitro. Bone marrow (BM), spleen (S), peritoneal (P), and thioglycolate-stimulated peritoneal (Pthio) macrophages isolated from resistant C57BL/6 Cr (B6) mice consistently restrict HSV-1 macromolecular synthesis earlier in the viral replicative cycle than do macrophages isolated from the same tissue sources from more susceptible DBA/2Cr (D2) mice. B6-BM (BM macrophages from B6 mice) restrict HSV macromolecular synthesis at least at two points in the replicative cycle: 1) before the onset of alpha-protein synthesis and 2) between the onset of gamma 1 protein and DNA synthesis. D2-BM macrophages restrict HSV replication at about the time of DNA synthesis. B6-P macrophages restrict HSV replication shortly after gamma 1 protein synthesis, and D2-P macrophages inhibit the virus slightly later, but before DNA synthesis. B6-S macrophages restrict HSV replication at about the time of DNA synthesis, and D2-S macrophages inhibit replication after the onset of gamma 2 protein synthesis. Pthio macrophages are more permissive to HSV infection than BM, P, or S macrophages: restrictions in viral replication occur at the time of DNA synthesis in B6-Pthio macrophages, and after the onset of gamma 2 protein synthesis in D2-Pthio cells. These studies demonstrate that isolated macrophages from inbred mouse strains express intrinsic resistance to HSV infection that correlates with in vivo resistance to acute (lethal) infection. Intrinsic resistance to HSV-1 infection is due to restriction of viral macromolecular synthesis. HSV replication is inhibited in macrophages at multiple points in the viral growth cycle, depending on the tissue from which the cells are isolated.

Acute Disease↗

PubMed1989

Blood glutathione: a biochemical index of life span enhancement in the diet restricted Lobund-Wistar rat.

These experimental results demonstrate that dietary restriction in both conventional and germfree rats results in enhanced longevity compared to fullfed animals. This increase in median survival age was due to a delay of 8 months in the onset of mortality in the restricted rats. Thereafter the aging rates of the short-lived subpopulations were the same for both groups. However, the aging rate of the long-lived restricted subpopulation was greater. The blood glutathione profiles demonstrated that a GSH deficiency of aging occurred in both the restricted and the long-lived groups. These data confirmed in the rat the findings observed previously in mosquito, mouse and man and verified the generality of the GSH and longevity relationship. Of special interest is that the blood glutathione levels were consistently higher at all ages of the restricted compared to fullfed rats and decreased more slowly during senescence. These findings indicate a direct relationship between enhanced GSH status and increased longevity due to dietary restriction. Further this suggests that glutathione may be a molecular mechanism for the diet restriction and longevity phenomenon.

Aging↗

PubMed1988

Compliance with a restricted antimicrobial agent policy in a university hospital.

Compliance with a policy for use of antimicrobial agents that requires both oral approval from the infectious diseases service and completion of a restricted antimicrobial agent use form was evaluated in a 950-bed teaching hospital. The charts of patients for whom a restricted antimicrobial agent was ordered during four one-week periods between January 1987 and April 1987 were audited to determine whether completed use forms had accompanied orders for restricted antimicrobial agents. The validity of the information on completed forms was determined by comparing the information on the form with notes in patients' charts and through discussions with infectious diseases physicians. Two infectious diseases physician reviewers evaluated the appropriateness of prescribing of piperacillin and ceftazidime by analyzing data collected by pharmacists. Forms were submitted with 132 of 154 orders written for restricted agents; incomplete forms were received and accepted by pharmacists for 39 courses of therapy. The infectious disease service had not been contacted to approve use of a restricted agent in 25 cases. Eight of the 48 courses of piperacillin or ceftazidime therapy were deemed inappropriate despite initial infectious diseases approval. Compliance with a formal antimicrobial agent restriction policy at this institution has been good, but periodic re-education and follow-up monitoring appear to be necessary to ensure optimal use of restricted agents.

Anti-Bacterial Agents↗

PubMed1987

[Effects of overall food restriction on embryo-fetal development in the rat].

The effects of different levels of food restriction on the fetal-embryo development have been tested in rats (Sprague Dawley) weighing 250 g. Experimental groups received 100 (control), 75, 50 or 25% of mean daily consumed food containing 17% of proteins, either from the coupling (Day 1) or from the nestling (Day 6) and till the sacrifice (Day 21). The weight of the mothers and the fetus is diminished in function of the degree and the duration of the food restriction. The study of the maternal growth shows an adaptation to the food restriction as well as the pregnancy anabolism. The last one is not observed in the females presenting an early embryonic mortality. The nestling is not affected in any of the groups and the embryonic mortality is only observed at the highest restricted level in 1/10 female restricted from Day 6 on and in 5/10 of the rats restricted from Day 1 on. In these last ones, the emaciation between Day 1 and Day 21 after hysterectomy is 37% and the growth of the surviving fetuses is only 40% of the controls. Embryonic mortality most often precocious (before the 10th Day) shows a phenomenon of "all or none" and touches the entire litter of the females concerned; the others maintain a normal pregnancy. The fetal growth seems privileged as compared with the maternal growth. These restrictions have neither influenced the sex ratio, nor induced any specific teratogenic effect: the delayed ossification seems to be expressed precociously on the 5th sternebra.

Animal Nutritional Physiological Phenomena↗

PubMed1986

[Lipid composition of the placenta of rats with protein restriction and deficiency of essential fatty acids].

The influence of diet restriction and EFA deficiency during pregnancy in the rat on the lipid and phospholipids composition of the placenta was investigated. Female virgin albino Wistar rats weighing 130 +/- 4 g, were assigned to three equivalent groups. Prior mating and during pregnancy each group of rats received the following regimen: Animals in the Control Group (C) were fed a 25% casein diet in ad libitum quantities; the dietary Restricted Group (D) received the same control diet in amounts calculated to approximate 50% (g/100 g rat) of the intake of group C; the Deficient and Restricted Group (DD) rats were fed a restricted amount of EFA deficient diet. On the 21st day of gestation pregnant animals were sacrificed. The foetuses and placentae obtained by caesarium section were isolated and weighed. A 50% food restriction before and during pregnancy resulted in a significant decrease in phospholipid contents (p less than 0.05); severe EFA deficiency superimposed to 50% food restriction, moreover induced significant changes in the fatty acid pattern of phospholipids, decreasing n3 and n6 fatty acids and increasing eicosatrienoic acid. There was an accumulation of triglycerides in the placenta of rats fed on the EFA deficient diet. In the two restricted groups fetal weight was reduced, but although in the DD group, placental weight was not affected, litter size was dramatically reduced.

Animals↗

PubMed1985

Induction of Kb-restricted anti-influenza cytotoxic T cells in C57BL mice: importance of stimulator cell type and immunization route.

C57BL/6 mice generate influenza-specific cytotoxic T cells (Tc) which are predominantly restricted to Db. The induction of a Kb-restricted response in H-2b mice has been controversial. We show here that the magnitude of Kb-restricted anti-influenza Tc responses is affected by the type of stimulator cell. Both in vivo and in vitro, secondary responses in the spleen show strong selection for Db-restricted Tc. However, limiting dilution analyses show that intranasal (i.n.) influenza infection primes Kb- as well as Db-restricted Tc in C57BL mice at a ratio of 1:2--but different cell types acting as stimulator cells vary in their ability to induce secondary Kb-restricted influenza-specific Tc (B lymphoblasts greater than macrophages greater than spleen cells greater than T lymphoblasts). Thus, the site of infection and antigen presentation can determine the MHC restriction of T-cell responses.

Animals↗

PubMed1984

T cell-accessory cell interactions that initiate allospecific cytotoxic T lymphocyte responses: existence of both Ia-restricted and Ia-unrestricted cellular interaction pathways.

The specificity of the T-accessory cell interactions that initiate primary allospecific cytotoxic T lymphocyte (CTL) responses were found to be surprisingly diverse and of three distinct major histocompatibility complex (MHC) specificities, involving responder T cell recognition of: a) self-Ia accessory cell determinants, b) allo-Ia accessory cell determinants, or c) allo-K/D accessory cell determinants. Any one of these T-accessory cell interactions was sufficient to initiate allospecific CTL responses. It was observed that when accessory cells did not express foreign class I MHC determinants, primary allospecific CTL responses were invariably initiated by Ia-restricted T-accessory cell interactions. In contrast, it was observed that when accessory cells did express foreign class I MHC determinants, primary allospecific CTL responses could be initiated by Ia-independent T-accessory cell interactions that were specific for allogeneic, but not self, K/D determinants and that did not involve recognition of polymorphic Ia determinants. The MHC specificities of the T-accessory cell interactions that initiate primary allospecific and primary trinitrophenyl (TNP)-self CTL responses were also compared. It was observed that primary allospecific and primary TNP-self CTL responses could be initiated by self-Ia-restricted T-accessory cell interactions, and that in both responses the Ia determinants that the responding T cells recognized as self-specificities on the accessory cell surface were those that their precursors had encountered on radiation-resistant thymic elements in their differentiation environment. In contrast to the initiation of primary TNP-self CTL responses that required the activation by accessory cells of Ia-restricted T helper (TH) cells, allospecific CTL responses could also be initiated by class I-restricted T cells specific for accessory cell K/D determinants. Interestingly, such class I-restricted T cells present in primary responder cell populations were triggered only by recognition of allogeneic, but not self, K/D accessory cell determinants, even when the accessory cells were modified with TNP. Thus, the present study demonstrates that primary allospecific CTL responses, but not TNP-self CTL responses, are initiated by Ia-restricted or Ia-independent cellular interaction pathways. These results raise the possibility that unprimed class I-restricted TH cells that mediate the Ia-independent cellular interaction pathway may predominantly express an allospecific, but not a self + X-specific, receptor repertoire. Possible mechanisms by which these distinct T-accessory cell interactions initiate primary allospecific CTL responses are discuss

Animals↗

PubMed1984

Recognition of H-2Kb mutant target cells by Moloney virus-specific cytotoxic T lymphocytes from bm13 (H-2Db mutant) mice. I. Full recognition of Kbm11 by Kb-restricted CTL.

In C57BL/6 (B6, H-2b) mice, the secondary in vitro CTL response against Moloney leukemia virus is restricted and regulated by the H-2Db locus. B6.C-H- 2bm13 ( bm13 ) mice, however, carrying a mutation at the Db locus, show an increased H-2Kb-restricted CTL response without a demonstrable CTL component restricted by the mutant Dbm13 molecule (D----K shift). These purely Kb-restricted bm13 virus-specific CTL were incubated with a series of Kb mutant virus-infected target cells to study the effect of the mutations at the target cell level. Of six Kb-mutant virus-infected target cells tested, bm1 cells were not recognized and bm8 cells were recognized only marginally by bm13 virus-specific CTL, whereas bm3 , bm5 , bm6 , and bm11 cells were fully recognized. Thus, the bm3 , bm5 , bm6 , and bm11 Kb mutants fully share the relevant H-2K restriction specificities with H-2Kb, whereas the bm1 mutant totally and the bm8 mutant almost completely lack these specificities. This result differs markedly from the restriction site relationships among B6 and these Kb mutants in other antigenic systems. The most striking example concerns the bm11 mutant, which is fully recognized by Moloney-specific CTL, but not at all by Sendai, minor H (H-3.1, H-4.2), and sulfhydryl hapten-specific CTL. Monoclonal anti-H-2Kb antibody B8-3-24 inhibited virus-specific lysis by bm13 CTL of all Kb virus-infected mutant target cells to which this antibody binds. Lysis of bm5 and bm11 but not of bm3 target cells was inhibited, in line with the fact that B8-3-24 antibody does not bind bm3 . On the other hand, not only bm5 and bm11 but also bm3 virus-infected target cells blocked virus-specific lysis to the same extent as syngeneic bm13 target cells. Therefore, bm13 virus-specific CTL populations do not recognize the discrete cluster alteration in the Kbm3 molecule, as identified by antibody B8-3-24. The bm1 and the bm8 mutations, which have structural alterations in completely different sites of the Kb molecule, show complete or almost complete loss, respectively, of Kb-Moloney restriction sites. This finding supports the notion that these virus-specific CTL recognize conformational determinants rather than linear amino acid sequences.

Animals↗

PubMed1993

[Investigation of agretopic motifs in T cell responses specific for pigeon cytochrome c related peptides and restricted to I-E molecules].

In our previous study, epitopic and agretopic residues of a peptide fragment deduced from pigeon cytochrome c43-58 (p43-58, AEGFSYTDANKNKGIT) and it's analogues in the T cell responses restricted to I-A molecules were determined. It has been shown that amino acid residue position 50 of the p43-58 works as an epitopic which contacts with T cell antigen receptor (TCR) and residues at positions 46 and 54 function as agretopes which contact with I-A molecules. In the present study, epitopic and agbretopic sites were analyzed in T cell proliferative responses that were restricted to the other class II, I-E, molecules. A peptide antigen, 46D50V54R, which had been prepared by substitution of amino acids at positions 46, 50 and 54 of p43-58 with aspartic acid (D), valine (V) and arginine (R), respectively was shown to induce class II restricted T cell responses in B10. A (3R) (I-Ab, I-Eb/k) but not in B10 (I-Ab, I-E-) mice. Similarly, 50V50R which had been prepared by substitution of amino acids at positions 50 and 54 with V and R, respectively induced T cell proliferation in B10. BR mice (I-Ak, I-Ek) but not in B10. A (4R) (I-Ak, I-E-) mice. These findings indicate that the 46D50V54R and 50V54R generate I-E restricted proliferative responses of T lymphocytes in I-Eb/k and I-Ek-carrying mice, respectively. Furthermore, it was shown that residue 50 functions an an epitope and residues 46 and 54 as agretopes in the I-E restricted responses. Almost identical results were obtained when I-E restricted responses of T lymphocytes were analyzed in B10. PL (H-2u) and B10. SM (H-2v) mice. However, sine no I-E negative counterpart strain for these two latter strains is available, complete analysis concerning the epitopic and agretopic functions has not been performed with B10. PL and B10. SM mice. The present findings demonstrate that the functional sites of the p43-58 analogues are preserved is the T cell responses restricted to each I-E haplotype studied. However, when most potent agretopic motif was determined in various mouse strains, the specific amino acid motifs on the agretopic positions were different among various I-E haplotypes. Furthermore, substitution of the epitopic residue showed no influence on the binding affinity between agretopic residues and class II molecules. Thus, these epitope and agretopes appear to function independently.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1994

Cytotoxic T cell repertoire selection. A single amino acid determines alternative class I restriction.

CTL responses are governed by intracellular Ag processing, affinity of peptides for MHC class I molecules, and the T cell repertoire. In this report we demonstrate that a class I Dd-restricted 10-mer CTL epitope within the gp160 envelope glycoprotein of HIV-1 strain IIIB (residues 318-327) contains a 9-amino acid peptide (residues 319-327), which efficiently binds to both the Dd and Ld class I molecules in vitro. The potential for broadening the naturally limited CTL response to include presentation on the Ld class I molecules in vivo was examined using a minigene-based vaccine strategy to insure cytosolic expression of "preprocessed" forms of the gp160 epitope. Immunization with recombinant vaccinia viruses (vac) expressing either the gp160 10 mer or 9 mer, both including an initiation methionine (M318-327 and M319-327, respectively), induced predominantly Dd-restricted CTL specific for native gp160. By contrast, recombinant vac expressing eight gp160 amino acids (M320-327) generated predominantly Ld-restricted CTL which are specific for synthetic gp160 peptides but not native gp160. The ability to induce Ld-restricted CTL suggests that the absence of an Ld-restricted response to native gp160 cannot be attributed to a limited T cell repertoire, but to inefficient processing of gp160 for presentation on Ld. The switch in class I restriction, controlled by a single amino acid within one epitope, demonstrates that nonanchor residues have a profound effect on differential MHC restriction and CTL induction. Thus, minigene-based vaccines expressing minimal epitopes may be useful in inducing a more heterogeneous CTL response than previously appreciated.

Amino Acid Sequence↗

PubMed1993

Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes. I. HLA-A2-restricted recognition of autologous and allogeneic tumor lines.

Metastatic renal cell carcinoma (RCC), like melanoma, belongs to the small group of human tumors in which partial or complete remission has been observed in some patients after treatment with various forms of immunotherapy. In contrast to melanoma, CTL showing MHC-restricted lysis of RCC have not been easily found among tumor-infiltrating lymphocytes (TIL). This has led to the suggestion by some that responses to immunotherapy are mediated predominantly by non-MHC-restricted effector cells. We have characterized an MHC-restricted, CD8+ CTL line obtained from an uncloned TIL population of a primary RCC using a low concentration of rIL-2; in fact, these CTL represented a majority of the short-term cultured TIL population. The CTL lysed autologous tumor cells but not normal kidney cells or target cells sensitive to non-MHC-restricted effector cells. In contrast, lymphokine-activated killer (LAK) cells grown in a high concentration of rIL-2 from the patient's PBL lysed autologous tumor and normal kidney cells in addition to several allogeneic tumors. The TIL could be expanded optimally using an autologous tumor line retrovirally transduced with the human cDNA encoding IL-2. TIL were 20-fold more potent than LAK cells in eliminating the IL-2 expressing tumor cells in vitro. The cultured TIL utilized a restricted number of V alpha gene families, suggesting that they may recognize only a limited number of MHC-peptide complexes presented by autologous tumor cells. HLA-A2 was identified as an MHC restriction molecule for presentation of one tumor-derived peptide to these CTL. Only some allogeneic HLA-A2 RCC tumors were lysed. Sequencing of the second and third exons of the HLA-A2 alleles of these cells revealed that both heterogeneity in MHC and peptide availability influenced CTL recognition. These studies demonstrate that some RCC express common antigenic determinants that can be recognized by MHC-restricted CTL and open the possibility of defining the nature of RCC-derived peptides, which, combined with HLA-A2, can generate specific immune responses.

Antibodies, Monoclonal↗