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PubMed2002

Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation.

We have previously shown that the infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase (HSV-tk) gene is an efficient tool for controlling graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) effect. In addition to the GVL effect, the administration of donor HSV-tk(+) cells could have a clinical impact in promoting immune reconstitution after T-cell-depleted stem cell transplantation (SCT). To explore this hypothesis, we have investigated whether in vitro polyclonal activation, retroviral transduction, immunoselection, and expansion affect the immune competence of donor T cells. We have observed that, after appropriate in vitro manipulation, T cells specific for antigens relevant in the context of SCT are preserved in terms of frequency, expression of T-cell receptor, proliferation, cytokine secretion, and lytic activity. A reduction in the frequency of allospecific T-cell precursors is observed after prolonged T-cell culture, suggesting that cell manipulation protocols involving a short culture time and high transduction efficiency are needed. Finally, the long-term persistence of HSV-tk(+) cells was observed in a patient treated in the GVL clinical trial, and a reversion of the phenotype of HSV-tk(+) cells from CD45RO(+) to CD45RA(+) was documented more than 2 years after the infusion. Based on all this evidence, we propose a clinical study of preemptive infusions of donor HSV-tk(+) T cells after SCT from haploidentical donors to provide early immune reconstitution against infection and potential immune protection against disease recurrence.

Antigens, Viral↗
PubMed2004

Low autocrine interferon beta production as a gene therapy approach for AIDS: Infusion of interferon beta-engineered lymphocytes in macaques chronically infected with SIVmac251.

BACKGROUND: The aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon beta production in macaques chronically infected with a pathogenic isolate of SIVmac251. RESULTS: Two groups of three animals infected for more than one year with a pathogenic primary isolate of SIVmac251 were included in this study. The macaques received three infusions of their own lymphocytes transduced ex vivo with the construct encoding macaque IFN-beta (MaIFN-beta or with a vector carrying a version of the MaIFN-beta gene with a deletion preventing translation of the mRNA. Cellular or plasma viremia increased transiently following injection in most cases, regardless of the retroviral construct used. Transduced cells were detected only transiently after each infusion, among the peripheral blood mononuclear cells of all the animals, with copy numbers of 10 to 1000 per 106 peripheral mononuclear cells. CONCLUSION: Long-term follow-up indicated that the transitory presence of such a small number of cells producing such small amounts of MaIFN-beta did not prevent animals from the progressive decrease in CD4+ cell count typical of infection with simian immunodeficiency virus. These results reveal potential pitfalls for future developments of gene therapy strategies of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1981

Passive transfer of insulitis from the "BB" rat to the nude mouse.

The "BB" rat spontaneously develops insulitis, and an insulin-dependent diabetic syndrome like that in man. Lymphocytes were isolated from blood and spleen of newly-detected "BB" diabetic rats and injected intraperitoneally (IP) into athymic nude mice. Of 72 mice receiving single injections 37% showed insulitis, with 13% of islets examined being affected, and mean intensity of 1.9 +/- 0.3 (on a scale of 0 to 3). In 12 mice receiving 3 separate injections of pooled blood and spleen lymphocytes, 58% showed insulitis, with 17% of islets affected, and mean intensity 2.5 +/- 0.3. Of 45 control mice either untreated, injected IP with saline, or injected with cells from nondiabetic control rats, only one showed mild insulitis. No random or post IP glucose hyperglycemia was observed. Thus, 1) passive transfer of insulitis has been achieved; 2) insulitis may be present without glucoregulatory disturbances; 3) the pancreatic B cell need not display abnormal membrane structure for it to be susceptible to involvement in the cell-mediated immune process; and 4) detailed studies are required to define the relationship of administered lymphocytes to the observed pathology.

Animals↗
PubMed1994

Engraftment of human lymphocytes and thyroid tissue into scid and rag2-deficient mice: absent progression of lymphocytic infiltration.

To study human autoimmune thyroid disease in an animal model we have investigated the in vivo survival of human thyroid tissues and functionality of human lymphocytes in severe combined immunodeficient (scid) mice and recombination-activating gene (rag2) knockout mice. We found successful engraftment of human thyroid tissues in both scid and rag2-deficient mice. However, when peripheral blood mononuclear cells were transplanted ip, human immunoglobulin production was poor in rag2-deficient mice compared to that in scid mice (mean human immunoglobulin G levels at 6 weeks, 0.2 +/- 0.2 microgram/mL in two of eight rag2-deficient mice compared to 20.8 +/- 7.0 micrograms/mL in seven of nine scid mice; P < 0.05). We, therefore, only pursued the further use of scid mice and transplanted them with thyroid tissue from patients with either Graves' disease (four patients) or Hashimoto's thyroiditis (one patient). At the functional level, we observed transiently increased thyroid hormone levels (T4 peaking at 5.4 +/- 0.2 microgram/dL compared to a normal level of 2.6 +/- 0.2 microgram/dL); human autoantibodies to human thyroglobulin, human thyroid peroxidase, and the human TSH receptor were also detected in thyroid-transplanted mice. In contrast to recent reports, histological examination of the thyroid explants showed no increase in the lymphocytic infiltrate compared to the original donor tissue, nor was there any thyroid follicular destruction observed. In fact, many of the transplants demonstrated a marked diminution in the infiltrates over time, with an absence of HLA-DR antigen expression by both T-cells and thyrocytes. Cotransplanted allogeneic thyroid tissues were unremarkable in terms of lymphocytic infiltrates and showed intact morphology. Taken together, these data point to a relative degree of T-cell inactivity within the thyroid explants from the scid mouse. Hence, a factor(s) present in the patient with autoimmune thyroid disease that activates their thyroid-specific T-cells may be absent in this murine model as presently constructed.

Animals↗
PubMed1979

Infiltration and survival: the behaviour of normal, invasive cells implanted to the developing chick wing.

The invasiveness of mouse lymphocytes and thymocytes, rabbit peritoneal neutrophil granulocytes (PMNs), mouse peritoneal macrophages (both activated and non-activated) and pig endothelial cells was assayed by implanting these cells to the chick wing bud. Cells of each type moved into the wing mesenchyme, although activated macrophages invaded poorly. PMNs were the most invasive cells and had moved well into the limb after only a few hours. PMNs, lymphocytes and thymocytes were ingested by wing mesenchyme cells. Endothelial cells, however, ingested chick blood cells. The implanted cells showed differences in ability to survive in the limb: PMNs disappeared rapidly, lymphocytes and thymocytes sometimes persisted for 24 h, while grafts of macrophages and endothelial cells were present at 24 h. Mechanisms which might be involved in the invasiveness of these cells, and also in their different abilities to survive in the chick wing, are discussed with particular reference to the production of plasminogen activator.

Animals↗
PubMed2003

Fate and functions of human adult lymphoid cells in immunodeficient mice.

Laboratory models enabling to study in vivo human leukocyte functions have been developed. Most of the models consist of human immunocytes transferred to mice homozygous for the scid mutation. Mice with additional immunodeficient-prone genetic background or with immunodeficiency-induced conditioning have also been used. Human grafts mainly consisted of human immune cells in suspension injected intraperitoneally, or in pieces of human organs containing immunocytes implanted subcutaneously. Cells in suspension could be easily manipulated in vitro before transfer to the animal, but disseminated within the mouse body. In opposition, human cells mostly remained within implantation areas of animals given human organ pieces. This favorizes cell interactions and helps for cell recovery after their in vivo passage. Moreover, the diversity of antibodies in animals transplanted with human lymphoid organ pieces appeared broader than that of mice transferred with lymphocytes in suspension. Spontaneous recall antibody and autoantibody productions have been generally observed in animals transferred with cells from donors with such antibodies. In vivo boosting of recall antibody by antigen has been most successful, but such a manipulation inconstantly boosted autoantibodies. Primary human T and B cell responses were difficult to obtain in xenochimeric animals, and success has been generally obtained by optimizing human immune response parameters, such as antigen presentation.

Animals↗
PubMed2004

Enhancement of allogeneic hematopoietic stem cell engraftment and prevention of GVHD by intra-bone marrow bone marrow transplantation plus donor lymphocyte infusion.

We examined the effect of intra-bone marrow (IBM)-bone marrow transplantation (BMT) in conjunction with donor lymphocyte infusion (DLI) on the engraftment of allogeneic bone marrow cells (BMCs) in mice. Recipients that had received 6 Gy of radiation completely rejected donor BMCs, even when IBM-BMT was carried out. However, when BMCs were IBM injected and donor peripheral blood mononuclear cells (PBMNCs) were simultaneously injected intravenously (DLI), donor cell engraftment was observed 7 days after BMT and complete donor chimerism continued thereafter. It is of interest that the cells of recipient origin did not recover, and that the hematolymphoid cells, including progenitor cells (Lin-/c-kit+ cells) in the recipients, were fully reconstituted with cells of donor origin. The cells in the PBMNCs responsible for the donor BMC engraftment were CD8+. Recipients that had received 6 Gy of radiation, IBM-BMT, and DLI showed only a slight loss of body weight, due to radiation side effects, and had no macroscopic or microscopic symptoms of graft-versus-host disease. These findings suggest that IBM-BMT in conjunction with DLI will be a valuable strategy for allogeneic BMT in humans.

Animals↗
PubMed1987

Management of infectious and immunological complications of acquired immunodeficiency syndrome (AIDS). Current and future prospects.

AIDS is caused by a newly recognised virus (human immunodeficiency virus; HIV) which induces a profound defect in cellular immune function associated with increased susceptibility to opportunistic infections and certain malignancies. The clinical presentation of HIV ranges from asymptomatic infection to severe immunodeficiency manifesting as severe life-threatening infectious diseases or malignancies. While major research efforts are being directed toward development of vaccine and discovery of effective antiretroviral drugs, clinicians are faced with AIDS patients with multiple and complicated medical problems including opportunistic infections and certain malignancies. Currently, efforts are directed toward early diagnosis, treatment, and prevention of recurrence of these opportunistic infections. The current approaches are reviewed in this article. Major recent developments in AIDS research include the isolation of the HIV on culture and the availability of the antibody test. Aside from vaccine and antiretroviral drugs, other measures that may be of benefit in the treatment of AIDS patients are immunological enhancement and reconstitution. Several studies are underway to evaluate antiviral agents in the treatment of HIV infection. Those undergoing clinical trial include suramin, ribavirin, antimoniotungstate, phosphonoformate and azidothymidine. Immune enhancers that have been used include alpha- and gamma-interferon and interleukin-2. HLA-matched lymphocyte transfusions and bone marrow transplantations have been used alone and in combination to replace the AIDS patient's defective immune system.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

The immunological status of allografts in the middle ear.

In a series of experiments using two inbred rat strains differing in respect of their major histocompatibility antigens, and a sensitive test for antibody directed against major histocompatibility antigens, it was shown that (i) grafts known to be highly immunogenic (10(7)) lymphocytes) regularly immunized their hosts when injected intratympanically; the immune response could not be ascribed to leakage of cells into either the external auditory meatus or the nasopharynx, (ii) immunization occurred at least partly via the regional lymphatics, (iii) single orthotopic or heterotopic incus grafts immunized their hosts sporadically, and (iv) the variable immunization which followed single ossicular grafts was due to their relatively low content of antigen.

Animals↗
PubMed2000

Induction of cardiomyopathy in severe combined immunodeficiency mice by transfer of lymphocytes from patients with idiopathic dilated cardiomyopathy.

Growing evidence suggests that autoimmune mechanisms play an important role in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). The aim of the study was to evaluate the effects of transfer of lymphocytes from patients with DCM into severe combined immunodeficiency (SCID) mice on the heart structure and function. Thirty CB-17 SCID (6-8 weeks old) mice were used and divided into 3 groups (n = 10). Mice were injected intraperitoneally with up to 25 x 10(6) peripheral blood lymphocytes (PBL) from either patients with DCM which contain human autoantibodies against cardiac beta1-adrenergic receptors and M2-muscarinic receptors (DCM group) or PBL from healthy controls (control-H group). Ten mice did not receive any injections and were used as baseline controls (control-N group). Echocardiography and morphological studies were performed seventy five days after the transfer. Results showed that in DCM group, left ventricle dimensions (LVD) in diastole were increased (4.2 +/- 0.1mm) as compared to both control-H group (3.8 +/- 0.1mm) and control-N group (3.6 +/- 0.1 mm) (p < 0.01). Further, there was a trend for increased LVD in systole. Fractional shortening was not different between groups. Histological evaluation revealed accumulation of human lymphocytes in the capillaries and scarce infiltration of the lymphocytes in the hearts from DCM group. Diffuse fibrosis was significant increased in DCM mice as compared to mice receiving PBL from normal subjects (2.2 +/- 0.3% vs. 0.8 +/- 0.1%, p < 0.01). In conclusion, transfer of the PBL from the patients with DCM was able to induce early stage of heart dilatation in SCID mice. These data provide for the first time the direct evidence supporting that the autoimmune mechanism is important in the pathogenesis of human DCM.

Animals↗
PubMed1990

Aberrant lymphocyte migration patterns in systemic lupus erythematosus (MRL/l, MRL/n) mice are independent of the micro-environment.

Mice with systemic lupus erythematosus (SLE) have unusual patterns of lymphocyte traffic characterised by diminished uptake of intravenously injected autoimmune cells into lymph nodes. This study examines the influence of the lymphocyte micro-environment on this aberrant migratory behaviour. To evaluate lymph node lymphocyte-endothelial interactions which can affect lymphocyte distribution without the in vivo influence of liver and spleen, the in vitro high endothelial venule (HEV) binding assay was used. Lymph node HEV binding of autoimmune MRL-lpr/lpr (MRL/l) and MRL(-)+/+ (MRL/n) lymphocytes was increased when compared with CBA/T6 lymphocytes and contrasted with diminished lymph node uptake noted in vivo. This was independent of the lymph node source (MRL/l, MRL/n, CBA/T6) onto which the lymphocytes were overlaid. To examine the influence of the microenvironment on in vivo traffic, 21Cr-labelled lymph node cells from normal CBA/T6 mice were injected into sex-matched MRL/l, MRL/n and CBA/T6 recipients. The distribution of cells was the same in each recipient strain suggesting that the micro-environment had little influence on the lymphocyte trafficking profiles of autoimmune mice. This study supports the view that aberrant lymphocyte migration in autoimmune mice results from defects intrinsic to the lymphocyte population and not the micro-environment.

Age Factors↗
PubMed1985

Effect of antilymphocyte serum and neonatal thymectomy upon onset of diabetes in the Chinese hamster.

Prediabetic Chinese hamsters were treated with antilymphocyte serum (ALS), or thymectomized in order to test the hypothesis that beta-cell loss leading to diabetes in this animal model was related to cell-mediated autoimmunity. In addition, passive transfer of diabetes from the Chinese hamster to the nude mouse was attempted by transplantation of lymphocytes. Treatment of prediabetic Chinese hamsters with ALS or thymectomy did not alter development or severity of diabetes in this animal model. Lymphocytes from newly diagnosed diabetic Chinese hamsters did not cause hyperglycemia in nude mice. These three lines of evidence suggest that cell-mediated autoimmunity does not contribute to the etiology of diabetes in the Chinese hamster. The Chinese hamster remains a good model for the study of those forms of diabetes not related to cell-mediated autoimmune phenomena.

Animals↗
PubMed1981

The quantitative effects of the B blood group locus and sex linked histocompatibility antigen in chickens on G-v-H reaction.

The major histocompatibility locus in the chicken is the B locus with a minor histocompatibility antigen controlled by a gene (s) on the W chromosome. This study was designed to determine the quantitative effects of the B locus and the sex linked histocompatibility gene on splenomegaly of chick embryos after inoculation with adult male lymphocytes. The embryos and male lymphocyte donors had blood group genotypes designed B9/B9, B9/B11 so that nine donor-host combinations were used. When the donor and host were homozygous for different B alleles (B9 and B11) or different by one B allele (B9 or B11) the splenomegaly was 4 and 2 times greater, respectively, than the compatible donor and host. A greater splenomegaly was produced in male to female injections than in male to male injections. However, the histocompatibility antigen controlled by a gene(s) on the W chromosome was weaker than the controlled by the B locus.

ABO Blood-Group System↗
PubMed1983

Graft versus host response as influenced by the origin of the cell, age of chicken, and cellular interactions.

Mononuclear cells collected by Ficoll-paque or T cells collected by nylon wool elicited the same magnitude of graft versus host (GvH) response as mononuclear cells collected from the buffy coat (BC). Bone marrow, spleen, or thymic BC cells from day-old chickens did not produce a GvH response. The GvH ability of spleen and bone marrow BC cells increased rapidly during the first 4 weeks and then plateaued. Although at 4 and 12 weeks of age the GvH response produced by thymic BC cells was significantly less than spleen or bone marrow BC cells, thymic BC cells did produce a significant GvH response at these ages. Thymic BC cells from 11-month-old chickens showed significantly higher GvH response than those of previous ages. Corticosterone treatment of chickens eliminated the thymic cortex but did not enhance the GvH reactivity of thymic BC cells. Suppressor effect of thymic BC cells from day-old chickens was not detected. A synergistic effect was noted in the GvH reaction when thymic cells were combined with bone marrow or splenic BC cells of 4-week-old chickens.

Age Factors↗
PubMed2004

Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy.

The lack of persistence of transferred autologous mature lymphocytes in humans has been a major limitation to the application of effective cell transfer therapies. The results of a pilot clinical trial in 13 patients with metastatic melanoma suggested that conditioning with nonmyeloablative chemotherapy before adoptive transfer of activated tumor-reactive T cells enhances tumor regression and increases the overall rates of objective clinical responses. The present report examines the relationship between T cell persistence and tumor regression through analysis of the TCR beta-chain V region gene products expressed in samples obtained from 25 patients treated with this protocol. Sequence analysis demonstrated that there was a significant correlation between tumor regression and the degree of persistence in peripheral blood of adoptively transferred T cell clones, suggesting that inadequate T cell persistence may represent a major factor limiting responses to adoptive immunotherapy.

Cell Proliferation↗