scholarly journals Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4440-4448 ◽  
Author(s):  
Arnab Ghosh ◽  
Wolfgang Koestner ◽  
Martin Hapke ◽  
Verena Schlaphoff ◽  
Florian Länger ◽  
...  
Keyword(s):  
T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Leukemia Cell ◽  
Donor Lymphocyte Infusion ◽  
Graft Versus Leukemia ◽  
Life Threatening ◽  
Host Origin ◽  
Antigen Presenting

Abstract Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs in vitro with leukemia cell lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETCs resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD rates observed after the transfer of naive donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Manoj Patidar ◽  
Naveen Yadav ◽  
Sarat K. Dalai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Therapeutic Potential ◽  
Chimeric Protein ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Antigen Presenting

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.

Mycophenolate Acid Has a Negative Effect on the Maturation and Immune Function of the Murine Bone Marrow-Derived Dendritic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3808-3808
Author(s):  
Zhen Cai ◽  
Wenye Huang ◽  
Wenji Sun
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Function ◽  
De Novo ◽  
Th2 Cytokines ◽  
Negative Effect ◽  
Antigen Presenting

Abstract Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, currently widely used in allogeneic bone marrow transplantation. Its active metabolite, mycophenolic acid (MPA) is a noncompetitive, reversible inhibitor of the enzyme inosine 59-monophosphate dehydrogenase, which plays a major role in the de novo synthesis of guanosine nucleotides. Unlike other cells that also use the salvage pathway for purine biosynthesis, proliferating B and T cells are dependent on the de novo pathway generate guanosine. Thus, MMF exerts its immunosuppressive effects of lymphocyte proliferation. Recently, some studies found that MPA could inhibit the immun immune function of antigen presenting cells. Dendritic cells (DCs), the most potent antigen presenting cells with the unique ability to prime naive T cells, play a central role in antigen processing and presentation to induce T cell response in vitro and in vivo. This study is to evaluate the effects of MPA, the in vivo active metabolite of MMF, on the maturation and immune function of murine bone marrow-derived dendritic cells, and to explore the underlying mechanisms of MMF in graft versus host disease. Bone marrow-derived dendritic cells (DC) were cultured with GM-CSF and IL-4 in the presence of MPA at doses of 0.01 and 0.1μmol/L. The ability of the allostimulatory activities of the DCs on allogeneic T cells was assessed by MLR. IL-12 production in culture supernatant and the Th1/Th2 cytokines such as IL-2, IFN-g, IL-4 and IL-10 levels in mixed lymphocyte reaction (MLR) supernatant were examined by ELISA assays. The activity of NF-κB in DCs was measured with Western blot assays. Our results showed that DCs cultured in the presence of MPA expressed lower levels of CD40, CD80 and CD86, exhibited weaker activity of stimulating the allogeneic T cell proliferation and weaker in antigen presenting function with a concurrent reduction of IL-12 production. MPA-treated DCs stimulated allogeneic T cells to secrete higher levels of Th2 cytokines IL-4 and IL-10 but lower levels of Th1 cytokines IL-2 and IFN-g than did DCs not treated with MPA. The activity of NF-κB was decreased in DCs treated with MPA in a dose-dependent manner. We conclude that MPA, and hence MMF, exerts a negative effect on the maturation and immune function of in vitro cultured DCs, and drives a shift of Th1 cytokines to Th2 cytokines in MLR. This negative effect is associated with a decrease in NF-κB activity. Say something about the significance of this finding regarding GVHD.

scholarly journals Nanoparticles Engineered as Artificial Antigen-Presenting Cells Induce Human CD4+ and CD8+ Tregs That Are Functional in Humanized Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Sophia Giang ◽  
David A. Horwitz ◽  
Sean Bickerton ◽  
Antonio La Cava
Keyword(s):  
T Cells ◽  
Lupus Erythematosus ◽  
T Regulatory Cells ◽  
Antigen Presenting Cells ◽  
Plga Nanoparticles ◽  
Nsg Mice ◽  
Artificial Antigen ◽  
Antigen Presenting

Artificial antigen-presenting cells (aAPCs) are synthetic versions of naturally occurring antigen-presenting cells (APCs) that, similar to natural APCs, promote efficient T effector cell responses in vitro. This report describes a method to produce acellular tolerogenic aAPCs made of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and encapsulating IL-2 and TGF-β for a paracrine release to T cells. We document that these aAPCs can induce both human CD4+ and CD8+ T cells to become FoxP3+ T regulatory cells (Tregs). The aAPC NP-expanded human Tregs are functional in vitro and can modulate systemic autoimmunity in vivo in humanized NSG mice. These findings establish a proof-of-concept to use PLGA NPs as aAPCs for the induction of human Tregs in vitro and in vivo, highlighting the immunotherapeutic potential of this targeted approach to repair IL-2 and/or TGF-β defects documented in certain autoimmune diseases such as systemic lupus erythematosus.

scholarly journals Targeting Antigen Presenting   Cells to Treat Autoimmune  Inflammation

2021 ◽  
Author(s):  
◽  
Aras Toker
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mhc Class Ii ◽  
T Cell Proliferation ◽  
Target Cells ◽  
Antigen Presenting

<p>Glatiramer acetate (GA) is approved for the treatment of relapsing-remitting multiple sclerosis (MS), and can suppress experimental autoimmune encephalomyelitis (EAE), a murine model of human MS. GA treatment is associated with the induction of anti-inflammatory TH2 responses and with the antigen specific expansion of regulatory T cells that counteract or inhibit pathogenic events in MS and EAE. These T cell mediated mechanisms of protection are considered to be a result of modulation of antigen presenting cells (APCs) by GA, rather than direct effects on T cells. However, it is unknown if GA preferentially targets a specific APC subset or can act through multiple APCs in vivo. In addition, GA-modulated innate cells may also exhibit direct antigen non-specific suppression of autoreactive cells. One objective of this study was to identify the in vivo target cell population of GA and to assess the potential of the target cells to antigen non-specifically suppress immune responses. Fluorophor-labelled GA bound to monocytes after intravenous injections, suggesting that monocytes may be the primary target of GA in vivo. In addition, intravenous GA treatment enhanced the intrinsic ability of monocytes to suppress T cell proliferation, both in vitro and in vivo. The findings of this study therefore suggest that GA-induced monocytes may contribute to GA therapy through direct mechanisms of antigen non-specific T cell immunosuppression. A further objective of this work was to investigate the potential of an in vivo drug targeting approach. This approach was hypothesised to increase the uptake of GA by the target cells and substantially improve GA treatment through antigen specific mechanisms such as induction of TH2 or regulatory T cells. Targeting antigens to professional APCs with an anti-MHC class II antibody resulted in significantly enhanced T cell proliferation in vitro. However, no EAE suppression occurred when GA was targeted to MHC class II in vivo. In addition, targeting GA specifically to monocytes also failed to suppress EAE. These findings suggest that GA treatment may selectively modulate monocytes to enhance their ability to inhibit autoreactive T cells, which could be part of the mechanism by which GA ameliorates MS. Targeting GA to a specific cell type may not be a powerful approach to improve treatment, because increased proliferation of GA specific T cells is not sufficient for disease suppression, and conjugation to antibodies may functionally reduce GA to a mere antigen devoid of immunomodulatory capacity.</p>

Expansion and Transformation of Primary Acute Lymphoblastic Leukemia Cells into Antigen-Presenting Cells using a Novel Culturing System Enables the Generation of Leukemia-Reactive T Cell Responses that Are Effective in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 303-303
Author(s):  
Bart A. Nijmeijer ◽  
Marianke L.J. Van Schie ◽  
Roel Willemze ◽  
J.H. Frederik Falkenburg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Primary Cells ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Antigen Presenting

Abstract Allogeneic cellular immunotherapy is generally ineffective in acute lymphoblastic leukemia (ALL). In vitro studies have suggested that this inefficacy may be the result of a lack of costimulatory molecule expression by ALL cells, resulting in the induction of T cell anergy. Activation of T cells by ALL cells that are transformed into adequate antigen-presenting cells (ALL-APC) may prevent the induction of T cell anergy and result in the generation of competent leukemia-reactive T cell responses for adoptive immunotherapy. However, in vitro modification of ALL cells was hampered by the fact that ALL cells from adult patients could not be cultured in vitro for prolonged periods of time. We have developed a novel serum-free culturing system for B-lineage ALL in which proliferation is initiated and sustained by ALL-cell derived growth factors. Long-term (>2 yrs) proliferation was induced in 12 out of 26 randomly selected primary samples from patients with ALL. The cell cultures ( Leiden cell lines) proliferated with a mean doubling time of 3.0 days (range 2.7–3.6 days). All Leiden cell lines presented the chromosomal abberations observed in the primary cells. The Leiden cell lines displayed an immune phenotype similar to the primary cells, exept for loss of CD34 expression. In vivo characteristics of Leiden cells were evaluated in NOD/scid mice. After intravenous inoculation, Leiden cell lines and primary cells showed identical homing patterns initially involving spleen and bone marrow, followed by the development of overt and progressive leukemia. A comparison of in vivo progression kinetics was performed for one of the Leiden cell lines and the corresponding primary cells. Weekly determination of leukemic cell counts in the blood of engrafted animals revealed that the cell line and the primary cells displayed similar doubling times in vivo of 6.3 and 7.7 days, respectively. To generate cells with improved antigen presentation function, Leiden cell lines were exposed to various activating agents. Stimulation with CpG containing oligonucleotides resulted in induction of CD40 in 9 out of 10 lines. Subsequent ligation of CD40 by culturing CpG-activated Leiden cells on fibroblasts expressing human CD40 ligand resulted in the induction of CD80 or CD86 in 7 of these 10 cell lines. To study the immune stimulatory properties of these Leiden ALL-APC, allogeneic HLA-identical T cells were first activated in vitro by coculturing these cells with either unmodified Leiden cells or with the corresponding Leiden ALL-APC for 3 days, and subsequently infused into groups of 6 leukemic NOD/scid mice. While T cells cocultured with unmodified Leiden cells did not expand in vivo, T cells cocultured with Leiden ALL-APC expanded after infusion in 5 out of 6 animals. This expansion coincided with a 20–75% decrease in leukemic cell numbers in the blood. In conclusion, the novel serum-free culturing system enables long-term culture and manipulation of a significant fraction of primary human ALL. These Leiden cell lines can be modified into ALL-APC that display adequate antigen presenting function, preventing the induction of T cell anergy as demonstrated in vivo in the NOD/scid mouse model.

Effect of In Vivo Azacitidine on GvHD and Gvl: Mechanistic Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2537-2537
Author(s):  
Jaebok Choi ◽  
Julie Ritchey ◽  
Jessica Su ◽  
Julie Prior ◽  
Edward Ziga ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Leukemia Cell ◽  
T Cell Proliferation ◽  
Cell Trafficking ◽  
Alloreactive T Cells ◽  
Donor T Cells

Abstract Abstract 2537 Introduction: Regulatory T cells (Tregs) have been shown to mitigate graft-versus-host disease (GvHD) while preserving the beneficial graft-versus-leukemia (GvL) effect in animal models of allogeneic bone marrow transplantation (BMT). However, three major obstacles prevent their use in human clinical trials: the low numbers of Tregs, loss of suppressor activity following in vitro expansion, and the lack of Treg-specific markers to purify expanded Tregs. The locus of the Foxp3 gene, the master regulator of Tregs, is unmethylated and expressed only in Tregs. We have recently reported that the hypomethylating agent azacitidine (AzaC) induces FOXP3 expression in non-Tregs, converting them into Tregs in vitro and in vivo when administered after allogeneic BMT completely mitigating GvHD without abrogating GvL (Choi, et al Blood 2010). Three possible mechanisms for these effects include: 1) AzaC induces FOXP3+ Tregs, which in turn mitigate GvHD without abrogating GvL by regulating alloreactive donor T cells, 2) AzaC directly suppresses the proliferation of alloreactive donor T cells reducing GvHD, 3) AzaC alters donor T cell trafficking to GvHD target organs to prevent GvHD without altering interaction of donor T cells with recipient leukemia or trafficking of leukemic cells. Methods: Balb/c (CD45.2+, H-2Kd) were lethally irradiated one day prior to injection of T cell-depleted BM cells isolated from B6 (CD45.1+, H-2Kb) and luciferase-expressing A20 leukemia cells derived from Balb/c. Allogeneic donor T cells isolated from B6 (CD45.2+, H-2Kb) were given 11 days after BMT. AzaC (2 mg/kg) was administrated subcutaneously every other day (4 doses total) starting 4 days after T cell injection. In vivo bioluminescence imaging (BLI) was performed to assess leukemia cell localization. For T cell proliferation/trafficking analyses, Balb/c were lethally irradiated one day prior to injection of T cell-depleted BM cells isolated from B6 (CD45.1+). Allogeneic donor T cells isolated from B6 (CD45.2+) were transduced with Click Beetle Red luciferase and were given 11 days after BMT, followed by AzaC treatment as described above. BLI was performed to track the donor T cells. Results: While neither T cell or leukemia cell trafficking was affected by the AzaC treatment, proliferation of donor T cells was significantly reduced compared to mice treated with PBS. The observed reduced T cell proliferation is not likely due to the direct effect of AzaC on T cells since the AzaC treatment preserved GvL activity comparable with the PBS control group. In addition, T cells isolated from both AzaC and PBS groups were equally reactive against third party antigen presenting cells, based on mixed lymphocyte reactions and cytotoxic T lymphocyte killing assays. These data along with our previous report demonstrating that the AzaC treatment increases Tregs in vivo strongly suggest that the therapeutic effect of AzaC on GvHD and GvL are mediated by the AzaC-induced Tregs which preferentially target alloreactive T cells while preferentially sparing anti-tumor T cells. Currently, secondary transplantation of Treg-depleted/replete T cells isolated from AzaC/PBS-treated recipient mice is underway to further confirm that donor T cells in the AzaC-treated mice are fully functional and that alloresponses of donor T cells are regulated by AzaC-induced Tregs. Conclusions: In vivo administration of AzaC after donor T cell infusion mitigates GvHD while preserving GvL via peripheral conversion of alloreactive donor T cells to FOXP3+ Tregs that preferentially inhibit alloreactive T cells while sparing anti-tumor T cells. These data provides the foundation for future clinical trials using epigenetic therapy aimed at mitigating GvHD without abrogating GvL and overcoming HLA barriers. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Persistence of Peptide-induced CD4+ T cell Anergy In Vitro

1998 ◽  
Vol 187 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Kelli R. Ryan ◽  
Brian D. Evavold
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Tolerance ◽  
Single Amino Acid ◽  
Peptide Analog ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Antigen Presenting

Clonal T cell unresponsiveness, or anergy, has been proposed as a mechanism of peripheral tolerance in vivo, and as a potential means of curbing unwanted T cell responses. In this study, anergy was induced in a T helper cell (Th) clone reactive to hemoglobin (Hb) peptide 64–76 by coculture of the T cells with live antigen-presenting cells (APCs) and 74L, a peptide analog of Hb(64–76) that contains a single amino acid substitution of leucine for glycine at position 74, or with a low concentration of the agonist ligand. The anergic state was characterized by blunted proliferation and interleukin (IL) 2 production upon restimulation with Hb(64–76), and was not the result of impaired TCR/CD3 downmodulation. The addition of exogenous IL-12 transiently restored proliferation of the anergic lines, but removal of IL-12 from culture returned the T cells to their nonproliferative state. Interestingly, persistence of the anergic phenotype was observed despite biweekly restimulation with antigen, APCs, and IL-2. Thus, T cell unresponsiveness induced by a peptide produced a stable, persistent anergic state in a Th0 clone that was not reversible by stimulation with IL-2 or -12.

Hemophagocytic lymphohistiocytosis (HLH) and related disorders

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 127-131 ◽  
Author(s):  
Alexandra H. Filipovich
Keyword(s):  
T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Hematopoietic Cell Transplantation ◽  
Viral Infections ◽  
Clinical Findings ◽  
Antiinflammatory Therapy ◽  
Genetic Causes ◽  
Life Threatening ◽  
Genetically Determined ◽  
Antigen Presenting

Abstract Hemophagocytic lymphohistiocytosis (HLH), which has many genetic causes, is characterized by multi-system inflammation. HLH is a reactive process resulting from prolonged and excessive activation of antigen presenting cells (macrophages, histiocytes) and CD8+ T cells. Hemophagocytosis, which is mediated through the CD163 heme-scavenging receptor, is a hallmark of activated macrophages/histiocytes and is the characteristic finding for which the disorder was named. The majority of genetic causes identified to date affect the cytotoxic function of NK and T cells, crippling immunologic mechanisms that mediate natural immune contraction. The predominant clinical findings of HLH are fevers (often hectic and persistent), cytopenias, hepatitis and splenomegaly. Due to the life-threatening implications of the diagnosis of genetically determined HLH, antiinflammatory therapy, often consisting of steroids, etoposide or antithymocyte globulin (ATG), should be instituted promptly, followed by curative hematopoietic cell transplantation. Secondary HLH, associated with autoimmune disorders or viral infections in teens and adults, also carries a significant mortality rate and should be managed in consultation with specialists familiar with the diagnosis and treatment of such disorders.

scholarly journals Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules

1981 ◽  
Vol 154 (5) ◽  
pp. 1652-1670 ◽  
Author(s):  
LH Glimcher ◽  
DL Longo ◽  
I Green ◽  
RH Schwartz
Keyword(s):  
T Cells ◽  
Culture Conditions ◽  
Primary Response ◽  
Secondary Response ◽  
Mouse Serum ◽  
Lymphocyte Response ◽  
Radiation Induced ◽  
Antigen Presenting

A system has been described that produces a murine syngeneic mixed lymphocyte response (MLR) comparable in magnitude to an allogeneic MLR. The responder cells in these cultures exhibit the classic immunologic characteristics of both memory and specificity. Studies using radiation-induced bone marrow chimeras of F(1) {arrow} parent type indicated that, similar to many other T cell-mediated immune responses, the response of the T lymphocytes in the syngeneic MLR was major histocompatibility complex-restricted and was determined by the environment in which the T cells matured. Using responder T cells from F(1) {arrow} parent chimeras and stimulator cells from H-2 recombinant strains, it was possible to map the genes involved in the stimulation to the K and/or I regions. In addition, blocking studies with monoclonal anti-Ia antibodies suggested that in the B10.A strain the critical molecules were products of both the I-A(k) and I-E(k) subregions. The issue of whether the syngeneic MLR is directed solely at self I-region antigens or whether the response represents proliferation to an unknown antigen in association with self I-region determinants was also addressed. Secondary syngeneic MLR were successfully performed in normal mouse serum and with stimulator cells prepared in the absence of bovine serum albumin to rule out the possibility that xenogeneic serum antigens were involved in the stimulation. The possibility that the syngeneic MLR might represent a secondary response to environmental antigens was eliminated by using germ- free mice as a source of stimulator cells and by demonstrating that spleen cells from unimmunized, fully allogeneic chimeras (B10.A {arrow} B10) could generate a normal syngeneic MLR even though such chimeras could not be primed to respond to any foreign antigens unless supplemented in vivo with a source of antigen-presenting cells syngeneic to the B10 host. The possibility that the syngeneic MLR was a primary response to a foreign antigen was considered unlikely because by using our culture conditions we could not obtain a primary antigen response or a secondary antigen response after in vitro priming to a variety of potent foreign antigens. Finally, the possibility that the syngeneic MLR represents a response to a variety of minor histocompatibility self antigens in association with self Ia molecules was eliminated by showing that the secondary responses to H-2 compatible, non-H-2 different strain (A/J vs. B10.A and C3H, or BALB/c vs. B10.D2 and DBA/2) were comparable to the secondary responses to syngeneic stimulators. Thus, we conclude that the target antigens in the syngeneic MLR are solely determinants on self Ia molecules, although the functionally equivalent possibility of a single, nonpolymorphic, minor self antigen seen in association with self Ia molecules cannot be excluded.

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