Eran Eilat

Prevention of Systemic Lupus Erythematosus-Like Disease in (NZBxNZW)F1 Mice by Treating with CDR1- and CDR3-Based Peptides of a Pathogenic Autoantibody

Two peptides based on the complementarity-determining regions (CDR) of a pathogenic murine anti-DNA antibody were employed in an attempt to prevent the spontaneous systemic lupus erythematosus (SLE)-like disease of (NZBxNZW)F1 mice. Female mice, at the age of 2 months, were injected with either the CDR1- or the CDR3-based peptides (pCDR1, pCDR3) subcutaneously or intravenously in aqueous solution for a total of 8–10 treatments. A reduction was observed in the total and pathogenic IgG2a and IgG3 anti-DNA antibody titers in the CDR-treated groups. Treatment reduced the number of mice that developed proteinuria and immune complex deposits in their kidneys. The severity of renal pathology was significantly reduced in the pCDR3 (P < 0.02) and pCDR1 (P ≤ 0.05) treated mice. Thus, both CDR-based peptides administered in aqueous solution were capable of preventing the SLE-like disease in (NZBxNZW)F1 mice, although the beneficial effects of pCDR3 appeared to be more pronounced than those of pCDR1 in the treated mice.

Immune activation in non-treated suicidal major depression

In the following study we have analyzed cytokine secretion of T-cells of suicidal and non-suicidal depressed patients and healthy controls. It was found that T-cells of suicidal depressed patients have Th1 characteristics, while T-cells of non-suicidal depressed patients have Th2 characteristics. Th1 environment is associated with most of autoimmune diseases. It is thus speculated that Th1 activation in suicidal depression may reflect a unique form of autoimmune suicide.

Immune response of SLE patients to peptides based on the complementarity determining regions of a pathogenic anti-DNA monoclonal antibody.

We have examined the humoral and cellular responses of SLE patients to peptides based on the complementarity-determining regions (CDR) of a monoclonal anti-DNA antibody with a major idiotype-16/6 Id, in comparison to their responses to the whole 16/6 Id-bearing antibody. Sera of 63% of the SLE patients had antibodies that bound the 16/6 Id, 80% had antibodies to one of the CDR-based peptides, and 40% of the patients reacted with both CDRs. Sera of only a few controls reacted with either the 16/6 Id (6%) or the CDR based peptides (4%) (P < 0.01). Peripheral blood lymphocytes (PBL) of 39% of the patients proliferated in response to the 16/6 Id or to one of the CDR-based peptides (37%), while in the control group the proliferation rates were 66% to the 16/6 Id and 59% to one of the CDR-based peptides (P < 0.05). The correlation between (both) the humoral and cellular immune responses to the CDR-based peptides and to the 16/6 Id suggests the relevance of these peptides to the 16/6 Id and provides additional information on the pathogenic moiety of the latter antibody.

Characterization and role in experimental systemic lupus erythematosus of T-cell lines specific to peptides based on complementarity-determining region-1 and complementarity-determining region-3 of a pathogenic anti-DNA monoclonal antibody.

Peptides based on the complementarity‐determining region 1 (CDR1) and CDR3 of an anti‐DNA monoclonal antibody (mAb) carrying the 16/6 idiotype (Id) were shown to induce experimental systemic lupus erythematosus (SLE) in susceptible mouse strains. In the present study, T‐cell lines specific to the pCDR1 and pCDR3 peptides were established in BALB/c and in SJL mice, respectively. The T‐cell lines were characterized and analysed for their pathogenicity upon administration to syngeneic mouse strains. Both T‐cell lines expressed the αβ T‐cell receptor (TCR) and the CD4+ CD8– phenotype. Additionally, both cell lines secreted interleukin (IL)‐4 and IL‐10 upon stimulation with their specific peptide, thus belonged to the T helper 2 (Th2) subset. Upon immunization, the pCDR3‐specific T‐cell line induced experimental SLE in SJL mice. The animals produced high levels of autoimmune anti‐DNA and antinuclear protein antibodies, as well as anti‐16/6 Id antibodies (Abs). Furthermore, the mice developed clinical manifestations, including leukopenia, proteinuria and accumulation of immune complex deposits in their kidneys. The pCDR1‐specific T‐cell line failed to induce SLE when injected into BALB/c mice. It is thus suggested that pCDR3 is an immunodominant epitope in experimental SLE and that pCDR3‐specific T cells initiate autoimmunity, leading to SLE, probably via epitope spreading.

Short note: Can depressive patients exploit the immune system for suicide?

It is suggested that patients with depression can exploit their immune system for suicide. This could be done passively by reducing the ability of the immune system to overcome factors threatening the integrity of the body, or actively by directing the immune system towards self constituents.

A Peptide Based on the CDR1 of a Pathogenic anti-DNA Antibody is more Efficient than its Analogs in Inhibiting Autoreactive T Cells

A peptide based on the sequence of the complementarity determining regions 1 (pCDR1) of a pathogenic murine monoclonal anti-DNA antibody (5G12) that bears the 16/6 Id, was synthesized. This peptide was shown to be immunodominant in BALB/c mice, and induced a mild lupus-like disease upon immunization. Furthermore, the pCDR1 when injected in a soluble form was capable of inhibiting the proliferation of lymph node cells primed to either the peptide or the anti-DNA, 16/6 Id antibodies of either murine (5C12) or human (16/6 Id) origin. We have designed and synthesized 39 analogs based on pCDRI with single amino acid substitutions. Out of the above, two analogs, namely, Asp14 and Ser16 inhibited the proliferative responses of a pCDR1-specific T cell line to its stimulating peptide by more than 50%. These two analogs were therefore further studied. Administration of analog Ser16 concomitant with the immunization with pCDR1 inhibited efficiently the proliferative responses of lymph node cells to pCDR1, although pCDR1 was more efficient in its inhibitory capacity. Neither of the analogs were capable of inhibiting significantly the proliferative responses to the human monoclonal anti-DNA antibody with the 16/6 Id whereas pCDR1 did so efficiently. Thus, pCDR1 is more efficient than all its tested analogs in immunomodulating SLE associated immune responses.