Page 288 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 18 Regulatory Immune Cells 269

activated, as during spring and summer compared with winter-
Autoimmunity time. Addition of IL-4 can attenuate the CD25 Treg-mediated
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As discussed above, natural Foxp3 CD4 Tregs are engaged in suppression of Th2 clones in vitro in the same way as IL-2, which
active suppression of autoimmune disease, since their depletion may provide an explanation for the insufficient control of ongoing
results in spontaneous development of autoimmune diseases in allergic responses by Tregs. Individuals with or without allergies
rodents. Furthermore, genetic anomaly of Foxp3 function can harbor allergen-specific, IL-4–producing effector T cells, IL-10–
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be a direct cause of autoimmune diseases in humans, as exempli- producing Tr1 cells, and CD25 Tregs, but in different proportions.
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fied in IPEX syndrome. A reduction of Foxp3 Tregs in number The balance between Th2 and certain Treg populations may,
or function has been reported in systemic autoimmune diseases, therefore, dictate whether clinical allergy will develop. Indeed,
such as SLE, Sjögren syndrome, antineutrophil cytoplasmic in the setting of curative specific allergy immunotherapy (SIT),
antibody (ANCA)–associated vasculitis, Kawasaki disease, systemic allergen-specific IL-10–producing T cells can be induced. Fur-
sclerosis, psoriasis, autoimmune hepatitis, myasthenia gravis, and thermore, children who “grow out” of their allergy to cow’s milk
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IBD. Of note, type II autoimmune polyglandular syndrome, have higher numbers of CD4 CD25 T cells specific for
which resembles the systemic disease induced in nude mice β-lactoglobulin compared with children with clinically active
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reconstituted with splenocytes devoid of CD4 CD25 T cells, is allergies. This suggests that certain allergies can be cured by the
also characterized by Treg functional deficiency. However, studies induction or expansion of antigen-specific Tregs and that the
of MS and type 1 diabetes did not detect any differences between balance between Tregs and effector T cells is of importance to
patients and controls, and conflicting data have been reported prevent allergeis. 30
in rheumatoid arthritis (RA) with regard to both function and
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numbers of CD25 high Tregs. The accuracy of the identification Transplantation
of Tregs must be taken into account in these human studies, The ultimate goal of organ transplantation is to establish tolerance
since CD25 and Foxp3 are also expressed to some extent by to allogeneic organ grafts as effectively and stably as to self-tissues,
activated non-Treg T cells in humans. but without the need for continuous general immunosuppres-
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A general observation is that FOXP3 Tregs increase in number sion (Chapter 81). Needless to say, Tregs have sparked a lot of
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at the site of inflammation. In the case of RA, synovial fluid attention in this area of research. CD25 Tregs were first shown
from patients with ongoing RA was found to contain increased to suppress GvHD in murine models of allogeneic bone marrow
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numbers of Foxp3 CD25 Tregs compared with the levels in transplantation. Similarly, nude mice transplanted with allogeneic
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peripheral blood. CD25 Tregs from the synovial fluid of patients skin rejected the graft when reconstituted with CD4 CD25 T cells
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with RA are largely functional, although their numbers or sup- alone but retained the graft when large enough numbers of CD25
pressive function is apparently not enough to halt the inflam- Tregs were cotransferred. In humans, attempts have been made
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matory process. In contrast, CD25 Tregs obtained from the to prevent GvHD in bone marrow transplantation and induce
blood of patients with MS reportedly have decreased abilities to graft tolerance in organ transplantation with the use of purified
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suppress proliferation of effector T cells. In summary, reduced CD25 Tregs. Another potential way to promote the induction
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levels of FOXP3 CD25 Tregs in peripheral blood are not a general of Tregs in organ transplantation is to evaluate the effects of
finding in autoimmune diseases and may not necessarily reflect various immunosuppressants in terms of altering the balance
the actual conditions at the site of inflammation. However, if between Tregs and effector T cells. Different immunosuppressants
Treg subsets defined by expression levels of CD45RA and Foxp3 target different pathways in cell metabolism and can therefore
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are assessed, cytokine secreting Foxp3 non-Tregs increase in have different effects on cell populations that behave in dissimilar
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active SLE. Dynamic changes of Treg subsets in various auto- ways, such as effector T cells and Tregs. Dosage and timing of
immune states remain to be investigated. administration, as well as specific drug combinations, seem to
be a promising angle of transplantation immunotherapy with
Allergic Disease the purpose of inducing graft tolerance and preventing graft
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CD25 natural Tregs play an important role in suppressing the rejection. Tregs have been shown to home to, and reside within,
development of allergic reactions to innocuous environmental the graft, which is stably accepted once a dominance of Tregs has
substances. This is best illustrated by IPEX syndrome, which is become established. Treg-mediated transplantation tolerance is
accompanied not only by organ-specific autoimmune diseases not a systemic phenomenon but, rather, is localized to the graft,
but also by severe eczematous dermatitis, high levels of serum and as such, it would not incur the dangers that accompany
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immunoglobulin E (IgE), and sometimes eosinophilia. Indeed, general immunosuppression. 31
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FOXP3 CD25 Tregs from the blood of healthy donors without
allergies suppress both proliferation and production of Th2 Tumor Immunity
cytokines when challenged with specific allergens in vitro. If the It is now well known that many of the tumor-associated antigens
same experiment is performed with Tregs from individuals with recognized by a patient’s T cells are normal self-constituents,
allergies, a marked difference is seen, as these Tregs fail to indicating that antitumor immune responses are within the range
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downregulate Th2-related responses to allergens. IL-10 production of FOXP3 Treg control. Therefore the presence of natural Tregs in
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by the FOXP3 Tregs, Tr1 and Breg, has been implicated in the the normal immune system may not only prevent autoimmunity
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control of allergic responses. 29 but also hamper immune surveillance of cancer. In fact, FOXP3
Since the suppressive ability for polyclonal stimuli is retained Tregs, in particular, highly suppressive FOXP3 high effector Tregs,
in patients with allergies, this deficiency is directly related to the are abundant in the tumor mass where they likely block any
allergen the individual is sensitized to and thus probably does immune response targeting malignant cells. Studies on human
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not reflect a general Treg deficiency. The inability to suppress malignancies have shown that the frequency of FOXP3 Tregs
Th2 responses induced by birch or grass pollen is aggravated is increased in tumors of, for example, metastatic melanoma or
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when the allergic reaction is ongoing and effector cells are fully pancreatic and lung cancers. Moreover, high levels of FOXP3