R. R. P. De Vries

T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes.

Type 1 diabetes seems to be an autoimmune disease in which T cells have a substantial role. A possible target antigen was suggested by the proliferation of CD4 T cells from a newly diagnosed patient in response to a 38 kD polypeptide of the insulin-secretory-granule membrane. To see whether this reactivity is widespread at disease onset, we have generated T-cell lines in vitro from peripheral blood mononuclear cells of nineteen children of caucasoid origin with newly diagnosed type 1 diabetes and sixteen healthy controls matched for age and HLA antigens. The procedure involved two cycles of incubation with a rat beta-cell tumour subcellular fraction enriched in secretory granules and plasma membrane components, followed by a proliferation assay. Fourteen (74% [95% confidence interval 49-91%]) of the patients cell lines showed a positive proliferative response on subsequent exposure to the islet-cell antigen preparation compared with only two (13% [2-38%]) of the controls (p = 3 x 10(-4); difference 61% [44-87%]). Two subjects who had high titres of islet-cell autoantibodies (ICA) without clinical diabetes produced responsive T-cell lines. Reactivity towards the 38 kD fraction of insulin-secretory-granule membranes was found only in patients (eight of ten responders tested; 95% CI 44-98%) and one ICA-positive non-diabetic subject. Detection of an ongoing autoimmune T-cell response might be useful diagnostically and could lead to prevention of diabetes through specific immunotherapy.

Influence of non-inherited maternal HLA antigens on occurrence of rheumatoid arthritis

Many HLA-associated diseases occur in patients not carrying the putative predisposing antigen. The suggestion that this might be due to disease heterogeneity is not sufficiently supported by available data. We hypothesise that HLA-DR4-associated genetic susceptibility to rheumatoid arthritis is due to an effect of DR4 on T-cell receptor repertoire expression and that the presence of antigen in the mother is capable of producing this effect in her children, even when DR4 is not inherited by them. To investigate this possibility we HLA typed 94 rheumatoid arthritis patients and their parents and 86 control families. An increased frequency, compared with controls, of non-inherited maternal HLA-DR4 was found predominantly in the mothers of DR4-negative patients. Unexpectedly, we also found an increased frequency of non-inherited maternal HLA-DR6 and a decreased frequency of non-inherited maternal HLA-DR3 in the mothers of DR4-positive patients. The results of our analyses are consistent with our hypothesis.

Autoreactive and immunoregulatory T-cell subsets in insulin- dependent diabetes mellitus

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is a T-cell mediated autoimmune disease. Several subsets of T-cells, in particular CD4+ and in vivo activate CD45RA+RO+ T-cells, have been shown to be increased at disease onset. The functional implications of these relative increases in CD4 T-cells were investigated. Methods. Subsets of T-cells were sorted on the basis of their activation status (CD45RA+ naïve cells, CD45RA+RO+ recently activated cells and CD45RO+ memory cells) and stimulated with autoantigens or recall antigen in vitro. Results. Proliferative responses to tetanus toxoid were primarily or exclusively observed in resting memory T-cells (CD45RO+). Autoimmune T-cell responses were, however, primarily measured in activated T-cells (CD45RA+RO+) in newly diagnosed Type I diabetic patients, whereas those with longer disease duration reacted to autoantigens with memory T-cells (CD45RO+) (p < 0.004). Interestingly, in non-diabetic control subjects not responding to autoantigens in the regular assay, considerable autoreactive T-cell responses were detectable after sorting in the CD45RO+ or CD45RA+RO+ lymphocyte subsets. Remixing these subsets showed that these autoimmune responses in activated cells could be down-modulated by CD45RA+ lymphocytes, whereas resting memory cells appeared unaffected by the suppressive CD45RA subset. Conclusion/interpretation. These results show that autoimmune T-cell responses can be linked to particular subsets which differ depending on clinical status. Furthermore, the CD45RA T-cell subset harbours lymphocytes potentially capable of suppressing autoimmune T-cell responses. The changes in responsiveness to exogenous insulin may help to unravel the mechanism by which isohormonal therapy could prevent the onset of Type I diabetes. [Diabetologia (1999) 42: 443–449]

T-lymphocytes and the pathogenesis of type 1 (insulin-dependent) diabetes mellitus

In the last few years considerable progress has been made with regard to the unravelling of the processes responsible for the destruction of pancreatic P-cells in the islets of Langerhans, leading to type 1 (insulindependent) diabetes mellitus. Important B-cell autoantigens have been identified, P-cell antigen specific Tcell reactivity has been described in humans, and several non-MHC linked susceptibility loci have been mapped in the NOD mouse. Attention to genetic predisposition to type 1 diabetes in humans has moved from HLA-DR to HLA-DQ, and in particular combinations of DQ alleles of both a and B, and interest is slowly moving to non-HLA loci. The result is, that although our knowledge of the molecular basis of the disease has increased, the complexity of the genetic association and molecular processes has increased simultaneously. In this review, the latest developments in our understanding of the pathogenesis of type 1 diabetes and their implications for immunotherapy and prevention of the disease are summarized.

An immunogenetic view of delayed type hypersensitivity

Abstract This review, the third in the series on cellular immune reactivity to tubercle bacilli in the centenary year of Kochs classical paper describing this phenomenon and its possible implications [1], represents an immunogenetic point of view. In fact this will be quite a broad point of view by an immunogeneticist who is not hampered by specific knowledge on therapy or prevention of tuberculosis. In this respect I probably do not differ very much from Robert Koch 100 years ago! An important difference, however, is that we think we now understand a great deal of the cellular and molecular basis of the immunological phenomena observed by Koch. Immunogenetics has contributed considerably to our current understanding and I will try to review that contribution here. Because thus far my main research interest has been in another mycobacterium, namely Mycobacterium leprae , I will use M. leprae and leprosy as an example to illustrate some ideas. The message of this review is that there is a reason for optimism: the knowledge recently gained by cellular and molecular immunologists as well as immunogeneticists has straightforward implications for the rational development of subunit vaccines and immunotherapeutic strategies.

1991 MACK FORSTER AWARD LECTURE REVIEW

In this paper I will review studies on the biological and clinical significance of the human leucocyte antigen (HLA) system, in particular my own studies on HLA and disease. This review is an edited version of the lecture presented at the European Society for Clinical Investigation (ESCI) meeting in Pisa on 5 April 1991. As with my lecture it is divided into three parts. The first is on genetic epidemiology of HLA and infectious diseases and specifically addresses the question: ‘What is the biological and evolutionary significance of the HLA polymorphism?’. The answer will be that it may be considered as a life insurance for premature death from infectious diseases. In the second part, which uses as scientific tools cellular and molecular immunology, the question is addressed: ‘What is the mechanism of HLA immune response gene phenomena?’ To this purpose I will discuss a model that we have studied in depth over the past ten years, namely leprosy, and explain that the results of these studies have implications not only for vaccine development but also for immunotherapy of autoimmune diseases. The latter will be discussed in the last section, which addresses the question: ‘How can we apply the knowledge on the function of HLA molecules, combined with the fact that certain HLA alleles are associated with immunopathological and autoimmune diseases, to the immunotherapy of these autoimmune diseases?’