Page 1146 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1112 Part NiNe Transplantation

There are significant differences between human and mouse
Tregs, in particular the differences in FOXP3 expression: In Biomarkers of Rejection or Tolerance
humans, FOXP3 is also expressed transiently by activated non- Concerns have been raised regarding the evaluation of tolerance
regulatory T cells that also upregulate CD25 expression. Thus induction protocols, such as those using cellular therapies in
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not all CD25 FOXP3 CD4 cells will be genuine Tregs, and recipients of kidney, heart, or pancreas, as an episode of acute
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therefore isolation strategies based on CD25 CD4 are likely to rejection could severely affect graft function and survival. In
be imperfect. Stable expression of FOXP3 in Tregs depends on these settings, most physicians are reluctant to withdraw immu-
DNA demethylation at the Treg-specific demethylated region nosuppressive drugs in the absence of validated biomarkers of
(TSDR), a conserved, CpG-rich region within the FOXP3 locus. transplantation tolerance and rejection prediction. Biomarkers
The TSDR is selectively demethylated in tTregs (which are more are thus needed to better evaluate the immune status of transplant
stable than pTregs), and therefore the methylation status of the recipients, determine the “tolerance signature” of recipients,
TSDR region can act as a marker for the quality and stability of predict and diagnose graft rejection noninvasively, and individual-
a Treg population. Cell-surface markers that can enrich for Tregs ize immunosuppressive therapy.
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have also been described. In humans, CD127 CD25 CD4 T Technical advances in multiparameter flow cytometry, antigen-
cells are characterized by a higher level of FOXP3 expression specific lymphocyte assays, and genome-wide analyses have led
and a more pronounced suppressive capacity. 70,71 Importantly, to the development of powerful and more standardized immu-
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ex vivo expanded CD25 CD4 and CD127 CD25 CD4 Tregs nomonitoring techniques to characterize alloimmune responses.
are effective at inhibiting vasculopathy in a humanized mouse Histological analysis remains the gold standard method by which
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model, whereas CD127 CD25 CD4 T cells are five times more to detect graft rejection, but graft biopsy is an invasive procedure
efficient than those not expressing a low level of CD127. 56 with inherent risks and so cannot be routinely performed for
A number of strategies for the isolation or enrichment of surveillance purposes. It is also associated with sampling error
human Tregs have been described, but there is no consensus as and interpretation biases.
to which strategy produces the optimal population for use in Molecular or cell-based biomarkers are being developed as
cell therapy applications. The most commonly used expansion alternative surveillance methods. 20,75 At present, it is notable that
protocol at present is based on stimulation by anti-CD3/anti-CD28 for the many biomarkers identified, there are discrepancies among
beads in the presence of high doses of recombinant IL-2, supple- data from different laboratories investigating the same parameter.
mented in some protocols with rapamycin. Despite the generation This is likely caused by differences in recipient and donor popula-
of sufficient numbers of Tregs for cellular therapy, this mode of tions, clinical management, and the laboratory techniques used
expansion is antigen nonspecific without any enrichment steps to perform the assays. Therefore it is of great importance that
for the cells of interest. The concept of expanding or generating the assays used to detect biomarkers are optimized, validated,
donor alloantigen-reactive Tregs is much more appealing and standardized and that candidate biomarkers are investigated
for clinical application in the setting of transplantation and a in large patient cohorts from different transplantation centers
number of studies have shown that donor alloantigen-reactive using the same shared and validated assays. 76
Tregs are more potent on a cell-per-cell basis at controlling
allograft rejection. Further work to ascertain the long-term ON tHe HOriZON
stability and plasticity of Tregs in vivo, as well as the potential
effects of Tregs in antitumor and antiviral immunities, as theoreti- Initiatives in Clinical Utilization of Tolerance
cally the infusion of large numbers of potent suppressive cells • Clinical introduction of antigen-specific regulatory T-cell therapy
may compromise the immune response toward infectious • Identification of tolerance signatures and predictors of rejection
pathogens and tumor cells. 73 • Use of immunomodulatory stem cell populations (i.e., mesenchymal
Several other immunomodulatory cell groups are currently stromal cells)
under investigation as potential tolerogenic therapies, such as
mesenchymal stromal cells (MSCs) and regulatory macrophages. Please check your eBook at https://expertconsult.inkling.com/
MSCs were originally isolated from the bone marrow but can for self-assessment questions. See inside cover for registration
now be isolated from almost any human tissue, and they possess details.
fascinating tissue repair and immunoregulatory properties.
Preclinical models indicate that MSCs can promote engraftment
of allogeneic cells, tissues, and organs as well as prevent and/or REFERENCES
treat rejection. Although there are no published reports, to date, 1. Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation
on their potential to induce tolerance in the setting of clinical of the human kidney between identical twins. J Am Med Assoc
SOT, their use as an induction therapy instead of anti-IL2R has 1956;160(4):277–82.
demonstrated a lower incidence of acute rejection, decreased 2. Salahudeen AK, Haider N, May W. Cold ischemia and the reduced
risk of opportunistic infection, and better estimated renal function long-term survival of cadaveric renal allografts. Kidney Int
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at 1 year. Regulatory macrophages have been used in two safety 2004;65(2):713–18.
trials in renal transplantation. Overall, these trials demonstrated 3. Andrade CF, Waddell TK, Keshavjee S, et al. Innate immunity and organ
that infusion of regulatory macrophages is feasible and that there transplantation: the potential role of toll-like receptors. Am J Transplant
69
is the potential for immunosuppression minimization. There 2005;5(5):969–75.
are several ongoing clinical trials examining the application, 4. Hart DN, Fabre JW. Kidney-specific alloantigen system in the rat.
Characterization and role in transplantation. J Exp Med
safety, and efficacy of cellular therapies, including those for the 1980;151(3):651–66.
prevention and treatment of GvHD in hematopoietic stem cell 5. Qureshi F, Rabb H, Kasiske BL. Silent acute rejection during prolonged
transplantation (HSCT) and the prevention of rejection in solid delayed graft function reduces kidney allograft survival. Transplantation
organ transplantation. (e.g., the ONE Study; www.onestudy.org). 74 2002;74(10):1400–4.