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PubMed2000

Branched-chain amino acid-enriched diet: effects on insulin secretion and cellular immune aggression.

Several reports have demonstrated that high-protein diets may have beneficial effects on experimental models of diabetes and have raised the possibility that branched-chain amino acids could play a role in these protective effects. We investigated the effect of a normoproteic, branched-chain amino acid-enriched diet (experimental diet) on insulin secretion from C57BL/6N mice transferred with splenocytes from diabetic syngeneic donors. Mice previously fed with the experimental or control diet received three intraperitoneal injections, every other day, of 5 x 107 viable mononuclear splenocytes obtained from control or diabetic donors. Results showed that mice fed with the experimental diet and transferred with "diabetic" splenocytes presented: i) normoglycemia, and (ii) significantly higher levels in both phases of glucose-induced insulin secretion and normal values of arginine-glucose-induced insulin secretion. To evaluate the in vitro cellular immune aggression, dispersed mouse islet cells were co-cultured with splenocytes from syngeneic diabetic mice. First, dispersed islet cells from mice on the experimental or control diet were co-cultured with splenocytes from control or diabetic mice on a commercial diet. In the presence of "diabetic splenocytes, dispersed islet cells from mice on the experimental diet presented a significantly lower in vitro cellular immune aggression. On the other hand, "diabetic" splenocytes from mice fed with the experimental diet produced a significantly reduced cellular immune aggression on dispersed islet cells. Our results showed that feeding branched-chain amino acids increased the capacity of beta cells to withstand a functional assault and diminished the extent of in vitro cellular immune aggression.

Amino Acids, Branched-Chain↗
PubMed2003

Should we re-examine the status of lymphocyte alloimmunization therapy for recurrent spontaneous abortion?

PROBLEM: In the human, lymphocyte alloimmunization immunotherapy (IT) has been proposed as a treatment for recurrent spontaneous abortion (RSA). This treatment has been the subject of debate for a long period of time. Recently, it has been proposed to extend such a treatment for implantation failure in humans, and I was asked to express my opinion on this topic. METHODS: I reviewed the evolution and theories and current paradigms in Reproductive Immunology and rationales proposed for IT. New discoveries show the complexity of implantation as a step by step developmental event, in mice and humans, and as such led me to re-examine paradigms currently evoked for extension of IT to implantation. Such a re-examination obviously leads me to re-question the basis of IT for RSA itself. CONCLUSIONS: I conclude that the Th1/Th2 paradigm, evoked as the current basis for IT, and as useful as it has been to explain pregnancy, is no longer sufficient. It is especially insufficient to explain the process of implantation, which involves inflammatory molecules and cannot fit in such a scheme. It ensues that alloimmunization has no scientific rationale for the treatment of human implantation as a whole, and should not be applied broadly at such a stage of pregnancy. Furthermore, its use in RSA should be re-examined.

Abortion, Habitual↗
PubMed2004

Shall we properly re-examine the status of allogeneic lymphocyte therapy for recurrent early pregnancy failure?

PROBLEM: How to evaluate immunological therapy advocated for recurrent spontaneous abortion and implantation failure. I was invited to comment on the opinion article of Chaouat (AJRI December 2003). METHODS: A critical examination of key beliefs and application of the principles of evidence and logic utilizing current data. RESULTS AND CONCLUSIONS: Although rationale has no bearing on efficacy of proposed treatments and is not sufficient justification for routine practice, insufficient attention to data concerning patient selection, insufficient attention to treatment methodology, and lack of full disclosure in some clinical trials needs to be corrected. A more systematic collection of follow-up data is needed.

Abortion, Habitual↗
PubMed2002

Photochemical treatment of donor lymphocytes inhibited their ability to facilitate donor engraftment or increase donor chimerism after nonmyeloablative conditioning or establishment of mixed chimerism.

Donor T-cells can provide a graft-versus-leukemia effect and help to promote donor engraftment after allogeneic BMT; however, these benefits can be outweighed by the ability of the cells to induce life-threatening GVHD. Photochemical treatment (PCT) of T-cells with S-59 psoralen and long-wavelength UV-A light can inhibit their proliferative capacity and significantly decrease their ability to induce acute GVHD after allogeneic BMT. PCT donor T-cells have been shown to facilitate donor engraftment in a myeloablative BMT model. In this study, we examined whether donor T-cells subjected to PCT ex vivo could retain the ability to facilitate engraftment or increase donor chimerism after nonmyeloablative BMT or after establishment of mixed hematopoietic chimerism. In a transplantation model in which mice were conditioned for BMT with sublethal (600 cGy) TBI, an infusion of PCT donor T-cells was unable to facilitate engraftment of donor BM. A BMT model was used in which a mixture of allogeneic and syngeneic marrow cells was infused into lethally irradiated recipients for establishment of mixed hematopoietic chimerism. The goal was to determine whether PCT donor splenocytes could increase levels of donor chimerism. Recipients of splenocytes treated with UV-A light only (no S-59 psoralen) and given at the time of BMT or in a donor lymphocyte infusion (DLI) had significantly higher levels of donor chimerism than did recipients of BM only. Although PCT donor splenocytes given at the time of BMT modestly increased donor chimerism, PCT donor splenocytes given in a DLI did not increase donor chimerism. A nonmyeloablative BMT model was employed for determining whether DLI given relatively late after BMT could increase donor chimerism. Recipient mice were conditioned for BMT with a combination of low-dose TBI (50 or 100 cGy) and anti-CD154 (anti-CD40L) monoclonal antibody for achievement of low levels of mixed chimerism. When control mixed chimeras were given a DLI 71 days after BMT, donor chimerism was significantly increased. In contrast, PCT of the donor cells eliminated the ability of the cells to increase donor chimerism after infusion. Together results from these 3 distinct BMT models indicate that PCT of donor T-cells significantly inhibited the ability of the cells to facilitate donor engraftment after nonmyeloablative BMT or to increase donor chimerism in mixed hematopoietic chimeras when the cells were administered in a DLI.

Animals↗
PubMed2002

Fas/CD95 is required for gastric mucosal damage in autoimmune gastritis.

BACKGROUND & AIMS: Experimental autoimmune gastritis (EAG), characterized by a gastric mononuclear cell infiltrate, mucosal cell damage, and autoantibodies to parietal cell-associated H(+)/K(+) adenosine triphosphatase, is a model for human autoimmune gastritis that leads to pernicious anemia. Previous in vitro studies have implicated Fas/CD95 in initiating damage to gastric mucosal cells in humans and an animal model of autoimmune gastritis. Here we used 2 in vivo animal models to examine the role of Fas in the development of mucosal cell damage in autoimmune gastritis. METHODS: We initiated EAG in BALB/cCrSlc mice by neonatal thymectomy and examined for Fas expression in the gastric mucosa by immunohistochemistry. To address the in vivo relevance of Fas in mucosal injury, we examined the stomachs and sera of BALB/cCrSlc lpr/lpr mice subjected to neonatal thymectomy and BALB/cCrSlc nu/nu lpr/lpr mice transferred with lymphocytes from gastritic BALB/cCrSlc mice. RESULTS: Fas expression was up-reguiated in parietal cells of mice with EAG. Neonatally thymectomized lpr/lpr mice were resistant to developing destructive gastritis compared with heterozygous and wild-type littermates. Nu/nu Fas-sufficient mice transferred with lymphocytes from thymectomized lpr/lpr mice developed destructive gastritis. Nu/nu lpr/lpr mice transferred with lymphocytes from gastritic mice developed a nondestructive gastritis. CONCLUSIONS: The observations that Fas is up-regulated in gastric parietal cells of mice with EAG and that Fas-deficient mice are resistant to development of destructive gastritis provide compelling evidence that Fas is required in vivo for development of gastric mucosal cell damage in autoimmune gastritis.

Animals↗
PubMed1999

Macrophage and lymphocyte homing in experimental diabetes.

Diabetes mellitus was induced in C57BL/6 mice by multiple low doses of streptozotozin (STZ). By transferring lymphocytes from these diabetic animals to healthy recipient mice insulitis can be induced in healthy recipient mice. On day 21 after the start of STZ-treatment splenic lymphocytes were separated in vitro and stained with the fluorochrom acridine red for adoptive transfer. The recipient mouse had been pretreated with a subdiabetogenic dose of STZ (5 mg/kg) i.p. 24 h prior to the lymphocyte transfer. With in vivo microscopy we measured the lymphocyte adherence to the endothelium of islets of the recipient mouse. After the administration of mAbs directed against LFA-1, ICAM-1, murine VCAM-1, VLA-4, MadCAM or alpha4,beta7-integrin prior to the cell transfer we could demonstrate a significant decrease of donor lymphocyte adherence in islets (P<0.01). The pretreatment of the recipient mice with STZ 24 h before the transfer of lymphocytes might attract macrophages to the islets. Therefore we pretreated the recipients with antibodies to cytokines or silica. mAb IFN-gamma, pAb TNF-alpha, pAb IL-1alpha or silica reduced lymphocyte adherence to islet endothelium significantly (P<0.01). The presented results support the following interpretation: The pretreatment of the recipient mice with the islet specific toxin STZ in subdiabetogenic doses attracts macrophages to the islets. The macrophages release cytokines leading to an increased expression of adhesion molecules on the endothelium of the islets. The consequence is lymphocyte homing selectively to the islets. The cascade of lymphocyte homing is complex and various pairs of adhesion molecules are involved. The discussion on the importance of the single pairs of adhesion molecules is irrelevant, since the cascade of lymphocyte homing can be disturbed by the application of a mAb to any one adhesion molecule involved in the cascade of lymphocyte homing.

Animals↗
PubMed1991

[Immunotherapy for the prevention of abortion].

It is now commonly assumed that a normal, successful pregnancy requires the specific recognition of the trophoblast by the immune system of the mother, resulting in production of protective or blocking factors (BF). In habitually aborting women, this recognition and/or BF production does not seem to occur. Immunisation of patients with leukocytes from the partner or from donors is postulated to induce these BF and to prevent fetal loss. After the exclusion of nonimmunological causes, 31 patients with at least three previous abortions and no pregnancies lasting longer than 16 weeks, were immunised with leukocytes from their partners. Eight women were already pregnant when treated, 15 became subsequently pregnant. Seventeen (= 74%) had uncomplicated pregnancies, six suffered again from early pregnancy loss. All 15 children, born so far had average birth weights and developed normally. The EAI-test (Power 1983) was of prognostic value: an increase of more than 50% in rosette inhibition activity in the serum of treated patients, correlated well with the successful outcome of their pregnancies; whereby the lack of this increase was associated with another early pregnancy loss. We could not confirm the reported of higher HLA-identity of couples with habitually aborting women, compared to fertile couples. HLA-typing (A, B, C, DR, and DQ) showed a higher proportion of identical allo-types in a group of 33 fertile couples than in a group of 44 couples with habitual abortions. This finding was significant (p less than 0.05).

Abortion, Habitual↗
PubMed2004

Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes.

Our recent clinical trials demonstrate that autologous cell transfer after lymphodepleting chemotherapy can cause the regression of large, vascularized tumors in patients with refractory metastatic melanoma. Eighteen of 35 patients treated with tumor-reactive lymphocyte cultures experienced an objective clinical response (>50% reduction in tumor), including four complete responders. In some patients, tumor regression was accompanied by a large in vivo expansion of the administered antitumor lymphocytes, which persisted in peripheral blood at >70% of total lymphocytes for many months after transfer. The cells capable of mediating tumor regression consisted of heterogeneous lymphocyte populations with high avidity for tumor antigens that were derived from tumor-infiltrating lymphocytes cultured for limited times in vitro. The success of this treatment likely results from the ability to infuse large numbers of activated antitumor lymphocytes into an appropriate host homeostatic environment depleted of regulatory T cells. These studies are elucidating the requirements for successful immunotherapy of patients with advanced metastatic disease and are leading to additional clinical trials with gene-modified lymphocytes.

Adult↗
PubMed1974

Incomplete restoration of the bursa-dependent immune system after transplantation of allogeneic stem cells into immunodeficient chicks.

Transplantation of allogeneic cells from bursa of Fabricius into cyclophosphamide-treated, immunodeficient chicks resulted in immunological tolerance to donor line skin grafts; graft-versus-host disease did not occur. Allogeneic bursal stem cells taken from 3-day-old donors induced restoration of bursal morphology, of antibody formation to Brucella abortus and of occurrence of pyroninophilic cells and immunoglobulin-bearing cells in the peripheral lymphoid tissues. Secondary response to sheep red blood cells and production of germinal centers were not restored. Transplantation of histocompatible bursal stem cells resulted in a complete reconstitution of the bursa-dependent lymphoid system, both in function and in morphology. Allogeneic postbursal stem cells taken from the bursa of 10-week-old donors had a reconstitutive effect only on the production of antibodies to Brucella. Transplanted stem cells maintained their functional potential in the allogeneic environment, since, when transferred back to histocompatible hosts, they displayed normal function. These findings indicate that a complete functional and morphological restoration of the bursa-dependent immune system cannot be achieved without identity of the donor and recipient at loci near to or identical with those determining the major histocompatibility antigens, even though graft-versus-host disease is avoided. This identity permits a full cooperation of the donor and host cells.

Age Factors↗
PubMed1974

Protection of lethally irradiated mice by spleen cells from neonatally thymectomized mice.

Long-lived, immunologically vigorous (C3H(f) x A(f))F(1) hybrids were produced after lethal irradiation by administration of spleen cells from C3H(f) or syngeneic donors. Further, neonatally thymectomized C3H(f) or A(f) strain donors reconstituted irradiated C3H(f) or (C3H(f) x A(f))F(1) hosts. In addition, C3H(f) spleen cells from nonthymectomized 10- to 15-day-old donors protected irradiated hybrid mice, but A(f) cells of young mice as well as of older mice produced graft-versus-host reaction and early death in irradiated C3H(f) or (C3H(f) x A(f))F(1) hybrids. Abrogation of secondary disease by treatment of irradiated mice with spleen cells from allogeneic neonatally thymectomized mice is possibly attributable to diminished immunologic competence of the cells grafted, followed by the development of immunological tolerance of the donor cells. Donor cells, receiving thymus influence in the recipient host after transplantation, could explain the long-lived immunologically vigorous radiation chimeras that did not experience graft-versus-host reactions. The findings of this study help to understand the differential susceptibility of A(f) and C3H(f) mice to development of tolerance to one another's antigens observed in prior investigations. It appears that, in these mice, the host thymus influences the maturation of the spleen cells from young mice or from neonatally thymectomized mice. However, this influence was often greater in mice given 767 rads than in those given 1046 rads. This differential influence is possibly attributable to irradiation damage to the thymus produced by the higher dose of irradiation. Spleen cells from neonatally thymectomized mice can be differentiated and expanded by the thymus of the host. The differential susceptibility of T(1), early differentiation stages, of thymus-dependent lymphocytes and T(2), late differentiation stages, of thymus-dependent lymphocytes to tolerance induction and immunostimulation, respectively, are proposed as the bases for these otherwise paradoxical influences.

Animals↗
PubMed1983

Ontogenic development of contrasuppression.

Using a xenogeneic graft-versus-host assay system, we have been able to document the sequential appearance of certain regulatory cells in newborn mice. Before birth, mouse spleen cells exhibit potent suppression that cannot be ameliorated by contrasuppressor cells. On the day of birth, the spleens contain equally potent suppressor cells, but these cells now can be inhibited totally by contrasuppressor cells. Between days 1 and 2 after birth, suppression, as picked up by our system, has disappeared. However, it can be found hiding behind contrasuppressor cells, as elimination of the latter cells with appropriate antisera reveals cells with the same suppressive potency as spleen cells taken 1 or 2 days earlier. Further, if the thymus is removed on the day of birth or 1 day later, the suppressor-obscuring cells do not appear. Thus, there appears to be an inherent ontogenic schedule that the thymus follows, which determines the time when different regulatory cells will emerge from it.

Aging↗
PubMed1992

Ectopic lymphokine gene expression in human peripheral blood lymphocytes in vivo.

An animal model to study the effects of ectopic expression of cytokines involved in cell growth and differentiation has been established. Retrovirus vectors containing the human interleukin 6 cDNA were used to produce high titer virus-producing lines. Human peripheral blood lymphocytes (hPBLs) were successfully infected with the retrovirus and engrafted into severe combined immunodeficient mice. The majority of the animals were engrafted with hPBLs, as determined by the presence of human glucose phosphate isomerase. Furthermore, six of seven mice engrafted with hPBLs infected with high titer virus and detectable hPBLs present in the spleen expressed the retroviral human interleukin 6 gene. Importantly, human interleukin 6 protein was expressed at physiologically significant levels in these mice. These results demonstrate that models for human disease and immunotherapy involving retrovirus-mediated gene transfer into human cells can be developed in mice.

Animals↗
PubMed1994

Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection.

The cultured T-cell line TIL1200, established from the tumor-infiltrating lymphocytes (TILs) of a patient with advanced metastatic melanoma, recognized an antigen on most HLA-A2+ melanomas and on all HLA-A2+ cultured neonatal melanocytes in an HLA-A2 restricted manner but not on other types of tissues or cell lines tested. A cDNA encoding an antigen recognized by TIL1200 was isolated by screening an HLA-A2+ breast cancer cell line transfected with an expression cDNA library prepared from an HLA-A2+ melanoma cell line. The nucleotide and amino acid sequences of this cDNA were almost identical to the genes encoding glycoprotein gp100 or Pmel17 previously registered in the GenBank. Expression of this gene was restricted to melanoma and melanocyte cell lines and retina but was not expressed on other fresh or cultured normal tissues or other types of tumor tested. The cell line transfected with this cDNA also expressed antigen recognized by the melanoma-specific antibody HMB45 that bound to gp100. A synthetic 10-amino acid peptide derived from gp100 was recognized by TIL1200 in the context of HLA-A2.1. Since the administration of TIL1200 plus interleukin 2 resulted in regression of metastatic cancer in the autologous patient, gp100 is a possible tumor rejection antigen and may be useful for the development of immunotherapies for patients with melanoma.

Adult↗
PubMed1996

Conditional reduction of human immunodeficiency virus type 1 replication by a gain-of-herpes simplex virus 1 thymidine kinase function.

The development of an effective vaccine for human immunodeficiency virus type 1 (HIV-1) would be a major advance toward controlling the AIDS pandemic. Several disparate strategies for a safe and effective HIV vaccine have been proposed. Recent data suggest that loss-of-function live-attenuated virus could be a safe lentivirus vaccine. Here, we propose a gain-of-function approach that can complement loss-of-function in enhancing the safety profile of a live-attenuated virus. We describe an example in which ganciclovir (GCV) was used to treat effectively nef(-)HIV-1 engineered to express herpes simplex virus (HSV-1) thymidine kinase (TK). This treatment was found to be highly efficient in controlling HIV-1 spread in tissue culture and in a small animal (hu-PBL-SCID) model. We demonstrate that one distinct advantage of GCV-HSV-TK treatment is the elimination of integrated proviruses, a goal not easily achieved with other antiretrovirals.

AIDS Vaccines↗
PubMed2000

Lymphocytic infiltration of bladder after local cellular immunotherapy.

BACKGROUND: This is a case report of a patient who received cellular immunotherapy, in the form of local injections of autologous stimulated lymphocytes (ASL) into individual tumors in the urinary bladder. A major consideration in cellular immunotherapy being the ability of immune cells to reach all target areas, we hypothesized that direct delivery of effector cells into individual bladder tumors might assure such access. METHODS: ASL were generated by exposing the patient's PBL to phytohemagglutinin and culturing them in the presence of IL-2 to expand the population. ASL were injected into the base of individual bladder tumors three times at intervals of 3 weeks. RESULTS: The patient died of a myocardial infarct, unrelated to cell therapy, 20 days after the third injection. An autopsy was performed. Histological sections of the bladder showed extensive lymphocytic infiltration of virtually the entire organ. DISCUSSION: No conclusions about the therapeutic efficacy of local immunotherapy using ASL are possible. Nevertheless, the observations reported, taken together with reports of therapeutic efficacy of other immunotherapy regimens in the management of bladder cancer, suggest that ready access of stimulated lymphocytes to all regions of the organ may account, in part, for the relatively high rate of therapeutic success reported for various immunotherapy regimens for this malignancy.

Aged↗