Deborah Benjamin

T cell vaccination in multiple sclerosis: A preliminary report

Multiple sclerosis (MS) is a presumed autoimmune disease of the central nervous system. Inoculation of attenuated T cell clones recognizing immunodominant regions of myelin autoantigens can protect animals from the induction of experimental autoimmune diseases. In this phase one trial, we investigated whether inoculations with attenuated T cell clones are feasible in humans for eventual trials with autoreactive clones and whether there are any associated immunologic effects. A total of seven inoculations with attenuated, autologous T cell clones isolated from the cerebrospinal fluid in four subjects with progressive MS was performed. No untoward side effects were observed. Immunologic studies suggested that the inoculation of autologous activated T cell clones followed by partial, short-term, immunosuppression as evidenced by a decrease of subsequent responses to stimulation via the CD2 pathway and increases in the autologous mixed lymphocyte response. We conclude that the use of attenuated autoreactive T cell clones appears feasible for further clinical trials in humans with autoimmune diseases.

Frequency analysis of CD4+CD8+ T cells cloned with IL-4.

The coexpression of both CD4 and CD8 molecules on T cells occurs in the peripheral blood at a low frequency and can be generated transiently on CD4+ peripheral blood T cells by treatment with lectin which induces CD8 biosynthesis and cell surface expression. We have cloned T cells in a nonselective fashion from normal subjects in the presence of either IL-2, rIL-4 and IL-2, or rIL-4 and have examined the phenotypic expression of CD4 and CD8. The addition of excess rIL-4 increased the expression of CD8 on the surface of CD4+ T cell clones but did not increase CD4 expression on CD8+ T cell clones. There were three patterns of CD4 and CD8 expression observed: high density CD8 with no CD4 expression; high density CD4 with low CD8 expression; or high density CD4 with higher cell surface CD8 expression which was regulated by the presence of rIL-4. CD4+ T cell clones originally cultured in IL-2 and rIL-4 and subsequently grown in IL-2 alone exhibited decreased expression of the CD8 molecule. The increased expression of CD8 did not correlate with NK activity or lectin-dependent cytotoxicity in an antigen independent system. In addition, rIL-4 alone or in combination with IL-2 appeared to accelerate the growth curve of T cell clones as compared to IL-2 alone. These results show that IL-4 can upregulate CD8 expression on CD4+ T cell clones while not effecting CD4 expression on CD8+ T cell clones. As class I MHC is the ligand for the CD8 molecule, expression of CD8 induced by IL-4 on CD4+ T cells may allow for increased nonspecific cell to cell contact during the course of an inflammatory response.

Secondary immune amplification following live poliovirus immunization in humans

Eight subjects inoculated orally with live attenuated poliovirus were investigated to study the effects of live virus infection on human T-cell responses. Proliferation to poliovirus and unrelated recall antigens were measured serially over a 3-week period. Five of eight subjects inoculated demonstrated a clear anamnestic response to poliovirus, but three did not. Only the five subjects demonstrating an anamnestic response to poliovirus were found to have augmented secondary immune responses to two unrelated recall antigens (tetanus toxoid and reovirus) and in the autologous mixed lymphocyte response (AMLR). No consistent changes were found in circulating T-cell surface activation antigens whether or not the subjects responded to poliovirus. These studies suggest that an asymptomatic poliovirus infection associated with immunization in humans can induce nonspecific secondary immune amplification as measured by in vitro T-cell proliferative response. This amplification pathway is a potential mechanism for immune responses against antigens other than those of the infecting virus.

Sequestration of virus-specific T cells in the cerebrospinal fluid of a patient with varicella zoster viral meningoencephalitis

The frequency of virus-specific T cells in the cerebrospinal fluid of a patient with viral infection of the brain and meninges was determined by using a single-T-cell cloning technique where a representative sampling of T cells was cloned from the cerebrospinal fluid of a patient with varicella zoster viral (VZV) meningoencephalitis. That the derived T-cell clones were in fact clonal was shown by demonstrating, on Southern blot analyses, unique rearrangements of the T-cell antigen-receptor beta-chain genes of each clone. Five out of the 15 of the T4+ (CD4), 0/4 of the T8+ (CD8), and 0/1 of the T4+T8+ T-cell clones proliferated to VZV, while no clones proliferated to mumps virus or myelin basic protein. There was no clonal expansion of any VZV-reactive T cell in this patients cerebrospinal fluid. As VZV meningoencephalitis is thought to be due to the reactivation of a dormant herpes zoster viral infection, it can be regarded as a secondary immune response. The presence of different T-cell receptor beta-chain gene rearrangements in each T-cell clone suggests that the T-cell response was polyclonal. These results demonstrate that a high frequency of polyclonal, T4+ antigen-specific T cells can be found in a naturally occurring, localized, immune response.