International Journal of Nephrology & Therapeutics
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This document discusses tolerance in renal transplantation. It begins by explaining that the adaptive immune system responds to transplanted organs by recognizing HLA molecules from the donor, triggering an alloimmune response. There are two mechanisms of tolerance: central tolerance occurs in the thymus, while peripheral tolerance involves inactivation of T lymphocytes in tissues. The document then reviews studies showing that splenectomy or splenosis can induce clinical tolerance to renal transplants in animal models by impacting antibody levels, regulatory T cells, and microchimerism. However, attempts to achieve robust tolerance through similar protocols in humans have largely failed due to the complexity of the transplantation immunobiology.
![SRL Nephrology & Therapeutics
SCIRES Literature - Volume 1 Issue 1 - www.scireslit.com Page - 005
The transplant of organs is one of the greatest therapeutic
achievements of the twentieth-century. In organ transplantation,
the adaptive immunity is considered the main response exerted to
the transplanted tissue, since the principal target of the immune
response are the MHC (major histocompatibility complex) molecules
expressed on the surface of donor cells [1]. However, we should not
forget that the innate and adaptive immunity are closely interrelated,
and should be viewed as complementary and cooperating. When a
human transplant is performed, HLA (Human Leukocyte Antigens)
molecules from a donor are recognized by the recipient’s immune
system triggering an alloimmune response Matching of donor and
recipient for MHC antigens has been shown to have a significant
positive effect on graft acceptance.
When a human renal transplant is performed, HLA molecules
(Human Leukocyte Antigens) from a donor are recognized by the
recipient’s immune system triggering an alloimmune response
[2]. This could happen by three recognizing mechanisms: First, an
indirect recognition: this type of mechanism has a dominant role
in chronic rejection; second, a direct recognition: this mechanism
determines a strong immune response in the acute rejection; and
third mechanism, a “semi-direct” recognition: that could be mediated
by immunoglobulin-like receptors of natural killer (NK) cells and can
mediate potent acute rejection.
On the other hand there are two mechanisms for tolerance: the
central and peripheral. In the central mechanism of tolerance the
events occur in T cells in the thymus and this is based on clonal
deletion and energy of cells (APCs). In the peripheral mechanism of
tolerance an inactivation of T lymphocytes in peripheral tissues such
as lymph nodes and spleen may be involved.
Tolerance in renal transplantation is an important issue for
physicians and researchers who have attempted different strategies to
promotetoleranceinrenaltransplantation,includingimplementation
of protocols in which tolerance induction have been a planned
objective before the transplant, and also several surgical procedures
for ABO-incompatible living kidney transplantation.
Tolerance in human transplantation can be defined in two ways.
Clinical tolerance (also referred to as clinical operational tolerance) is
the survival of a foreign organ or tissue (allogeneic or xenogeneic) in
a normal recipient in the absence of immunosuppression. Immune
tolerance is the absence of a detectable immune response against a
functional organ or tissue in the absence of immunosuppression [3].
Early evidence demonstrating that adult mice could be tolerant
of skin grafts after the induction of neonatal tolerance by the
introduction of splenocytes intraperitoneally was shown by Brent and
Medawar [4], in 1953. The central role of the thymus in mediating
cellular immunity and graft rejection was established by JFAP Miller,
who showed that nude mice [5] tolerated skin allografts because of
a marked deficiency of lymphocytes. Conversely, there have been
recent studies that show that spleen transplantation in pigs or dogs
has a tolerogenic effect on renal transplantation [6].
In our study [7], the splenosis and splenectomy resulted in the
induction of clinical tolerance to renal transplantation. Indicators
of tolerance included improved renal function (in the case of
splenosis) and higher recipient survival (in the case of splenectomy),
relative to controls receiving only transplantation. When splenosis
was performed, microchimerism is hypothesized as a tolerance
mechanism, while in the case of splenectomy the suggested
mechanism is a decrease in IgM and CD4+
CD25+
T lymphocytes.
The spleen is involved in the production of B lymphocytes and IgM,
and splenectomy thus can result in decreased antibody content and
increased tolerance. This effect could be considered analogous to the
effect of rituximab (anti-CD20+
monoclonal antibody), which avoids
acute rejection mediated by antibodies, resulting in a tolerogenic
effect. On the other hand, recent studies show the important role
of the spleen for the induction and maintenance of regulatory
CD4+CD25+
T cells which are important for self-tolerance. This
immune regulatory mechanism is known as non-specific suppression
of activation and differentiation, through the release of anti-
inflammatory cytokines. So, upon splenectomy, the activity of the
regulatory T cells is presumably affected, and this may simulate the
mechanisms of action of some currently used immunosuppressant
drugs, such as basiliximab and daclizumab (chimeric monoclonal
antibodies that selectively affect T lymphocytes).
On the basis of the promising results obtained in these animal
models, several tolerogenic protocols have been attempted in humans,
but most have failed to achieve robust and stable tolerance after renal
transplantation.Thisisduetothatthetransplantationimmunobiology
is very complex, because of the involvement of several components
such as antibodies, antigen presenting cells, helper and cytotoxic T
cell subsets, immune cell, surface molecules, signaling mechanisms
and cytokines; which play a role in the alloimmune response.
References
1. Ayala-García MA, González B, López A, Guaní E. The Major Histocompatibility
Complex in Transplantation. J Transplant. 2012; 842141.
2. Rossini AA, Greiner DL, Mordes JP. Induction of immunologic tolerance for
transplantation. Physiol Rev. 1999; 79: 99-141.
3. Ashton-Chess J, Giral M, Brouard S, Soulillou JP. Spontaneous operational
tolerance after immunosuppressive drug withdrawal in clinical renal
allotransplantation. Transplantation. 2007; 84: 1215–1219.
4. Billingham RE, Brent L, Medawar PB. Activity acquired tolerance of foreign
cells. Nature. 1953; 172: 603-606.
5. Miller JFAP. Effect of neonatal thymectomy on the immunological
responsiveness of the mouse. Proc R Soc Series B. 1962; 156: 415-428.
6. Dor FJ, Tseng YL, Kuwaki K, Gollackner B, Ramirez ML, Prabharasuth DD,
et al. Immunological unresponsiveness in chimeric miniature swine following
MHC-mismatched spleen transplantation. Transplantation. 2005; 80: 1791-
804.
7. Ayala-García MA, Soel JM, Díaz E, González B, Paz FJ, Cervantes F, et al.
Induction of tolerance in renal transplantation using splenic transplantation:
experimental study in canine model. Transpl P. 2010; 42: 376-380.](https://image.slidesharecdn.com/nt-id12-181025085116/85/International-Journal-of-Nephrology-Therapeutics-2-320.jpg)
International Journal of Nephrology & Therapeutics
- 1. Editorial Tolerance in Renal Transplantation - Ayala Garcia MA* Hospital Regional de Alta Especialidad del Bajio, Research Department, Mexico *Address for Correspondence: Marco Antonio Ayala Garcia, Hospital Regional de Alta Especialidad del Bajio, Research Department, Blv,. Milenio 130 Col. San Carlos La Roncha C.P. 37660 Leon, Guanajuato, Mexico, Tel: 477 267 2000 Extension 1707; Fax: 477 267 2000 Extension 1673; E-mail: [email protected] Submitted: 10 December 2015; Approved: 29 December 2015; Published: 31 December 2015 Citation this article: Ayala Garcia MA. Tolerance in Renal Transplantation. Int J Nephrol Ther. 2015;1(1): 004-005. Copyright: © 2015 Ayala Garcia MA. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. International Journal of Nephrology & Therapeutics
- 2. SRL Nephrology & Therapeutics SCIRES Literature - Volume 1 Issue 1 - www.scireslit.com Page - 005 The transplant of organs is one of the greatest therapeutic achievements of the twentieth-century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the principal target of the immune response are the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells [1]. However, we should not forget that the innate and adaptive immunity are closely interrelated, and should be viewed as complementary and cooperating. When a human transplant is performed, HLA (Human Leukocyte Antigens) molecules from a donor are recognized by the recipient’s immune system triggering an alloimmune response Matching of donor and recipient for MHC antigens has been shown to have a significant positive effect on graft acceptance. When a human renal transplant is performed, HLA molecules (Human Leukocyte Antigens) from a donor are recognized by the recipient’s immune system triggering an alloimmune response [2]. This could happen by three recognizing mechanisms: First, an indirect recognition: this type of mechanism has a dominant role in chronic rejection; second, a direct recognition: this mechanism determines a strong immune response in the acute rejection; and third mechanism, a “semi-direct” recognition: that could be mediated by immunoglobulin-like receptors of natural killer (NK) cells and can mediate potent acute rejection. On the other hand there are two mechanisms for tolerance: the central and peripheral. In the central mechanism of tolerance the events occur in T cells in the thymus and this is based on clonal deletion and energy of cells (APCs). In the peripheral mechanism of tolerance an inactivation of T lymphocytes in peripheral tissues such as lymph nodes and spleen may be involved. Tolerance in renal transplantation is an important issue for physicians and researchers who have attempted different strategies to promotetoleranceinrenaltransplantation,includingimplementation of protocols in which tolerance induction have been a planned objective before the transplant, and also several surgical procedures for ABO-incompatible living kidney transplantation. Tolerance in human transplantation can be defined in two ways. Clinical tolerance (also referred to as clinical operational tolerance) is the survival of a foreign organ or tissue (allogeneic or xenogeneic) in a normal recipient in the absence of immunosuppression. Immune tolerance is the absence of a detectable immune response against a functional organ or tissue in the absence of immunosuppression [3]. Early evidence demonstrating that adult mice could be tolerant of skin grafts after the induction of neonatal tolerance by the introduction of splenocytes intraperitoneally was shown by Brent and Medawar [4], in 1953. The central role of the thymus in mediating cellular immunity and graft rejection was established by JFAP Miller, who showed that nude mice [5] tolerated skin allografts because of a marked deficiency of lymphocytes. Conversely, there have been recent studies that show that spleen transplantation in pigs or dogs has a tolerogenic effect on renal transplantation [6]. In our study [7], the splenosis and splenectomy resulted in the induction of clinical tolerance to renal transplantation. Indicators of tolerance included improved renal function (in the case of splenosis) and higher recipient survival (in the case of splenectomy), relative to controls receiving only transplantation. When splenosis was performed, microchimerism is hypothesized as a tolerance mechanism, while in the case of splenectomy the suggested mechanism is a decrease in IgM and CD4+ CD25+ T lymphocytes. The spleen is involved in the production of B lymphocytes and IgM, and splenectomy thus can result in decreased antibody content and increased tolerance. This effect could be considered analogous to the effect of rituximab (anti-CD20+ monoclonal antibody), which avoids acute rejection mediated by antibodies, resulting in a tolerogenic effect. On the other hand, recent studies show the important role of the spleen for the induction and maintenance of regulatory CD4+CD25+ T cells which are important for self-tolerance. This immune regulatory mechanism is known as non-specific suppression of activation and differentiation, through the release of anti- inflammatory cytokines. So, upon splenectomy, the activity of the regulatory T cells is presumably affected, and this may simulate the mechanisms of action of some currently used immunosuppressant drugs, such as basiliximab and daclizumab (chimeric monoclonal antibodies that selectively affect T lymphocytes). On the basis of the promising results obtained in these animal models, several tolerogenic protocols have been attempted in humans, but most have failed to achieve robust and stable tolerance after renal transplantation.Thisisduetothatthetransplantationimmunobiology is very complex, because of the involvement of several components such as antibodies, antigen presenting cells, helper and cytotoxic T cell subsets, immune cell, surface molecules, signaling mechanisms and cytokines; which play a role in the alloimmune response. References 1. Ayala-García MA, González B, López A, Guaní E. The Major Histocompatibility Complex in Transplantation. J Transplant. 2012; 842141. 2. Rossini AA, Greiner DL, Mordes JP. Induction of immunologic tolerance for transplantation. Physiol Rev. 1999; 79: 99-141. 3. Ashton-Chess J, Giral M, Brouard S, Soulillou JP. Spontaneous operational tolerance after immunosuppressive drug withdrawal in clinical renal allotransplantation. Transplantation. 2007; 84: 1215–1219. 4. Billingham RE, Brent L, Medawar PB. Activity acquired tolerance of foreign cells. Nature. 1953; 172: 603-606. 5. Miller JFAP. Effect of neonatal thymectomy on the immunological responsiveness of the mouse. Proc R Soc Series B. 1962; 156: 415-428. 6. Dor FJ, Tseng YL, Kuwaki K, Gollackner B, Ramirez ML, Prabharasuth DD, et al. Immunological unresponsiveness in chimeric miniature swine following MHC-mismatched spleen transplantation. Transplantation. 2005; 80: 1791- 804. 7. Ayala-García MA, Soel JM, Díaz E, González B, Paz FJ, Cervantes F, et al. Induction of tolerance in renal transplantation using splenic transplantation: experimental study in canine model. Transpl P. 2010; 42: 376-380.