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Papers by Daniel Zimmerman

The Journal of Immunology

Background Development of a therapeutic vaccine for rheumatoid arthritis (RA) requires modulating... more Background Development of a therapeutic vaccine for rheumatoid arthritis (RA) requires modulating antigen specific inflammatory T cell responses that drive disease. RA can be initiated and driven by responses to multiple antigens but peptide vaccines usually contain few epitopes. The challenge is to elicit the appropriate responses by these vaccines. Method We used the proteoglycan (PG, aggrecan) G1 domain-induced arthritis model of RA. Mice were immunized with either one or two different DerG LEAPS vaccines containing PG epitopes (PG70 or PG275Cit) in Seppic ISA51vg adjuvant subcutaneously after signs of arthritis were noted. Mice were examined trice weekly for arthritis progression. At study end serum antibodies to the vaccine epitopes and splenic T-cell responses to PG G1 domain were determined. Results Immunization with DerGPG70 or DerGPG275Cit conjugate, alone or in combination, stopped the progression of disease. DerGPG275Cit was effective in protection but did not induce sign...

Biomedicines, 2021

Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances w... more Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies—(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)—to a newer approach—(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models. Whereas DMARDs ablate or inhibit specific proinflammatory cytokines or cells and jakinibs inhibit the receptor activation cascade for expression of proinflammatory cytokines, the LEAPS therapeutic vaccines specifically modulate the ongoing antigen-specific, disease-driving, proinflammatory T memory cell responses. This decreases disease presenta...

Vaccines

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic e... more Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit). The LEAPS peptides were administered alone or together in Seppic ISA51vg adjuvant to mice with PG G1 domain-induced arthritis (GIA), a mouse model of RA. Each of these LEAPS peptides and the combination modulated the inflammatory response and stopped the progression of arthritis in the GIA mouse model. Despite having a therapeutic effect, the DerG-PG275Cit vaccine did not elicit significant antibody responses, whereas DerG-PG70 (alone or with DerG-PG275Cit) i...

International …, 2008

We evaluated the efficacy of the Ligand Epitope Antigen Presentation System (L.E.A.P.S.™) in prev... more We evaluated the efficacy of the Ligand Epitope Antigen Presentation System (L.E.A.P.S.™) in preventing or treating experimental autoimmune myocarditis (EAM) in A/J mice. L.E.A.P.S. (here, J-My-1) is a conjugate of the myocarditogenic peptide of cardiac myosin MyHCα334352 (My-1) and J peptide, derived from the sequence of human β-2 microglobulin. Remarkably, early prophylactic (J-My-1 injected on days − 14 and − 7 before EAM induction), late prophylactic (J-My-1 injected on days 0, 7, 14, and 21), and therapeutic (J-My-1 injected on days 7, 14, and 21 or 10, 17 and 24) administration of J-My-1 significantly decreased the incidence and severity of EAM. However, extended therapeutic treatment was associated with anaphylaxis and death, corresponding with global immune activation associated with J-My-1 treatment. In J-My1-treated animals, we observed expanded numbers of activated CD69+ and CD44+ CD4+ and CD8+ T cells in the spleens. J-My-1 treatment also increased the proportion of CD1...

The Open Drug Delivery Journal

The ability of an oil-based carrier vehicle to act as an antigen delivery system via the oral and... more The ability of an oil-based carrier vehicle to act as an antigen delivery system via the oral and/or parenteral routes was investigated. The formulation consists of hydrophilic macromolecules (antigens) solubilised in oil phase, in the absence of water, by virtue of being wrapped in a sheath of phospholipid amphiphile. Results obtained demonstrate that the level of mucosal IgA antibodies detected in the stools of mice immunised orally with cholera toxin B fragment (CTB) or E. coli heat-labile toxin (LT) in oil is much higher than the level of IgA produced by mice immunised with CTB or LT alone. In addition, mice immunised orally with Y. pestis antigens (F1 and V) and CTB as immunostimulant in oil produce a significantly increased (p<0.02) systemic IgG response against both antigens (F1 and V) than mice orally immunised with F1, V and CTB without oil. Six out of ten mice immunised with F1 and V antigens in oil survived an aerosol challenge of 100 LD 50 doses of virulent Y. pestis. Furthermore, animals immunised sub-cutaneously with the HIV antigen (HGP-30) in oil induced much stronger humoral and cellular responses against the antigen than mice immunised with the antigen alone. Taken together, these findings indicate that oil can be used successfully as an antigen delivery system in vaccine formulations without the necessity of an aqueous phase or an emulsification process. This greatly enhances the stability and ease of production of a formulation manufactured for commercial use.

Journal of immunology research, 2017

The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine H... more The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine HER-2/neu66-74 H-2(d) CD8 T cell epitope covalently attached through a triglycine linker to the J-immune cell binding ligand (ICBL) (human β2 microglobulin38-50 peptide). The J-ICBL was chosen for its potential to promote Th1/Tc1 responses. In this proof-of-concept study, the ability of J-HER to prevent or treat cancer was tested in the TUBO cell-challenged BALB/c mouse model for HER-2/neu-expressing tumors. The J-HER vaccine was administered as an emulsion in Montanide ISA-51 without the need for a more potent adjuvant. When administered as a prophylactic vaccination before tumor challenge, J-HER protected against tumor development for at least 48 days. Despite eliciting protection, antibody production in J-HER-immunized, TUBO-challenged mice was less than that in unimmunized mice. More importantly, therapeutic administration of J-HER one week after challenge with TUBO breast cancer cell...

Clin Immunol, 2008

Ligand Epitope Antigen Presentation System (L.E.A.P.S. TM) is a new approach that converts an epi... more Ligand Epitope Antigen Presentation System (L.E.A.P.S. TM) is a new approach that converts an epitope as small as 8 amino acids into an immunogen. Attachment of the J peptide sequence, a peptide from the beta-2-microglobulin of the MHC class I molecule, to an epitope promotes T helper 1 immune responses. Previous studies in our labs showed that vaccines with epitopes of 8-20 amino acids from HSV-1, HIV, and M. tuberculosis conjugated to the J peptide were immunogenic and the HSV-1 vaccines elicited protection from challenge. Subcutaneous vaccination of mice with L.E.A.P.S. TM heteroconjugates containing an epitope from the HSV-1 gD protein (JgD) or an epitope from the HIV gag protein, H, (JH) in Seppic ISA51 was performed on day 0, sera was drawn on days 3, 10, and 24, cytokine levels were measured by RayBioR Mouse Cytokine Antibody Array I, quantitated by densitometry, and normalized to results for Seppic. Sera samples from JH and JgD injected mice showed a T helper 1-like cytokine response, with increased levels of IL-12 on day 3, increased levels of IFN-gamma levels by day 10 and day 24, and very low amounts of IL-10. The J peptide alone generated weak IL-12 and IFN-gamma production, but reduced IL-10 levels. Early induction of IL-12 followed by IFN-gamma production suggests that the J peptide heteroconjugates interact with dendritic cells which then activate T cells.

The Journal of Immunology, Oct 1, 1977

Lipid A, prepared from lipopolysaccharide, was labeled with 125 I. Such iodinated lipid A possess... more Lipid A, prepared from lipopolysaccharide, was labeled with 125 I. Such iodinated lipid A possesses the full mitogenic activity of untreated lipid A. Comparison of the 125 I-lipid A-binding activity of splenocytes and thymocytes from the same rabbit revealed that the extent of labeling of splenocytes was 10 to 20 times greater than that observed with an equivalent number of thymocytes. A similar preferential binding was detected in comparing cells in mouse and rat. Spleen populations depleted of adherent cells were essentially unaltered with regard to binding when compared to the original population. In addition, spleen cell populations enriched for thymus-derived cells (T cells) exhibited a marked loss of specific binding activity. On the other hand, spleen cell populations enriched for bone marrow-derived cells (B cells) exhibited the expected binding. The difference in binding behavior of B and T cell-enriched populations was confirmed by using three independent techniques to separate B and T cells. These findings are consistent with the mitogenic specificity of lipid A toward B cells rather than T cells and suggest that the observed cellular specificity resides in an early event in mitogenesis, i.e., binding of the mitogen.

The Journal of Immunology, Sep 1, 1973

Page 1. of November 21, 2010 This information is current as 1973;111;761-769 J Immunol Kern Danie... more Page 1. of November 21, 2010 This information is current as 1973;111;761-769 J Immunol Kern Daniel H. Zimmerman and Milton M-Secreting Cells of Immunoglobulin Emergence Cells: The in Vitro Differentiation of Lymphoid Subscriptions ...

Archives of Virology, May 1, 2002

The requirements for disease development in the mouse epidermal scarification-zosteriform model o... more The requirements for disease development in the mouse epidermal scarification-zosteriform model of HSV infection are likely to parallel those required for primary HSV disease of humans. HSV-1 strains, which are neuroinvasive in the mouse footpad model of HSV encephalitis, caused local site lesions within 3 days and secondary zosteriform lesions along the dermatome within approximately 5 days. HSV-1 strains, which are not neuroinvasive, failed to progress to zosteriform lesion development and local site lesions were mild or absent. Relative differences in the rate and extent of zosteriform lesion development paralleled the behavior of the viruses in the mouse footpad model of neuroinvasion. In conclusion, the viral properties which are important for neuroinvasiveness appear to also determine the ability of an HSV strain to cause zosteriform disease.