User:Kinkreet/Immunology/Costimulatory pathways in transplantation

In 1975, Lafferty and Cunningham proposed the activation of T cells is a two-signal process. CD4+ T cell activation (survival, clonal expansion and differentiation) requires the antigen presentation molecule Major Histocompatibility Complex (MHC) on the antigen presenting cell (APC) to bind to the T cell receptor, as well as a secondary (co-stimulatory) signal of the B7 family to bind to CD28 on the T cell. Both are required for activation, and the absence of CD28 leads to tolerance, which is mediated by mechanisms of clonal anergy, clonal deletion and regulation.

Alloimmunity
This co-stimulatory pathway is also observed in alloimmunity, where an individual gains an immunity against parts of another individual of the same species, perceiving it as foreign. Alloimmunity is the basis of all transplantation rejections. The alloresponse is split into two parts - the first is allorecognition of the antigen, the second is the effector mechanism mounted against it. The alloantigens are histocompatibility complex antigens, of which there are two types: Major Histocompatibility Complex (MHC, which are also called human leukocyte antigen (HLA) in humans) and minor histocompatibility antigens (mHAgs). Most rejections occur because the host sees the donor MHC as foreign, and treats it as another antigen (although MHC itself is involved in antigen presentation in the donor, it is not in the host), mounting an attack against the cell which presents it. But even if the MHCs do not mount an alloresponse, the mHAgs can still mount a response, which is weaker than a potential MHC response; mHAgs response is particular important in bone marrow transplantation. Once the CD4+ T cells initiates a response, it secretes cytokines to attract phagocytes such as macrophages, and CD8+ T cells to attack the foreign cells, and also help the B cells to turn into plasma cells so it can secrete highly specific antibodies against the antigens. To prevent this, tissue typing is performed to ensure the host can accept the donor organ.

But we can also induce tolerance of the transplanted organs by blocking out the co-stimulatory response. Historically, the targets for blockage has been CD28 and CD154 (which binds CD40). This is done with some success in rodents, but less so in larger animals and humans. The reason for this is likely to be the increased proportion of T memory cells, which activation is less dependent on the co-stimulatory pathways.

Types of Transplant Rejections
Medically, transplant rejections are split into three categories, defined by the timeline by which the rejection occurs: hyperacute rejection, acute and chronic rejection.

Hyperacute
Hyperacute rejections are mainly attributed to humoural immunity, which is when the adaptive system initiates an attack on the donor cells, partly aided by phagocytes and complement system inflaming the transplanted tissues and destroying it.

IgG plays a major role in hyperacute rejections; when the paratope of IgG binds to the epitope of the antigen, its conformational changes to allow it to bind a complement proteins and initiate the complement cascade. The complement system punches many holes into the foreign cell, this allows fluids to rush in and cell debris to be released into the environment. These cell debris are recognised as damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) of innate immune cells, causing them to secrete cytokines, some of which are chemokines that recruits more immune cells to the damaged site, and some of which are pro-inflammatory cytokines such as interleukin-1α (IL-1α) and tumour necrosis factor alpha (TNF-α), mainly secreted by macrophages and, less so, by neutrophils, epithelial and endothelial cells.

Acute
Acute rejections are mostly attributed to cellular immunity, where dendritic cells from the donor tissue migrates to the host’s lymphatic system, and its MHC peptides are presented to the host’s naïve helper T cells (CD4+). Along with the co-stimulatory pathway, it activates the T cells and this activates cytotoxic (CB8+) T cells, which binds to the donor’s MHC Class I and recognises it as the epitope, and this leads to signals which causes the cells in the donor tissue to undergo apoptosis. CD4+ helper T cells also binds to the MHC Class II and secretes inflammatory cytokines. Both hyperacute and acute responses have been suppressed more and more using newly developed immunosuppressive drugs, but chronic rejections are harder to suppress.

Positive
These pathways promote T cell activation, survival and/or differentiation. The best characterized costimulatory pathway of any kind is the CD28/B7 pathway, which is a type of positive co-stimulatory pathway.

CD28/B7
CD28 is a homodimer constitutively expressed on all T cells of mice, and on 95% of CD4 and 50% of CD8 T cells in humans. CD28 binds to B7.1 (CD80) and B7.2 (CD86) on antigen-presenting cells (APCs). B7.2 is constitutively expressed, whereas B7.1 is only expressed when induced. T cells are also known to express B7.

When CD28 binds to B7, it stimulates T cell survival, proliferation and cytokine production. Along with the signal from TCR binding, it can increases the expression of the IL2 receptor α-chain (CD25), which triggers the rapamycin (mTOR) pathway leading to proliferation; of CD40 ligand (CD40L and CD154), induces cytokine production, including IL2 and interferon-γ(IFN-γ), and expression of anti-apoptotic molecules (e.g. Bcl-xL).

When B7 binds to CD28 on the T cell, the T cell is activated. To control this activation, the binding of B7 also up-regulate cytotoxic T-lymphocyte-associated-antigen 4 (CTLA4 and CD152), a negative co-stimulatory molecule on the T cell surface which binds to B7, but with a greater affinity (complementarity) and avidity (strength) of binding than CD28. This tighter binding displaces CD28, and also prevent more CD28 from binding to B7. But unlike CD28 which stimulates TCR-dependent activation, CTLA4 binding inhibits it, leading to decreased proliferation and cytokine production. Using CTLA4, activation of the T cell is auto-regulated by the induction of CTLA4.

Furthermore, the downstream signal from CTLA-4 inhibits AKT, a key downstream intracellular signalling molecule of the CD28 pathway, and thus providing an additional step for CTLA-4 to inhibit CD28 function. The intracellular pathway of CTLA-4 also down-regulates B7 expression as well as inducing indoleamine 2,3-dioxygenase (IDO) expression, an enzyme involved in tolerance. CTLA4 is induced in T cells, but constitutively expressed in regulatory T cells (CD4+ CD25+ FoxP3+), which are also called suppressor T cells due to its ability to suppress CD28/B7 activation.

Negative
Inhibits T cell activation, survival and/or differentiation

TIM pathway
Involves in the regulation of T cell differentiation and regulatory T cell functions.

Immunoglobulins
e.g. CD28, CTLA4, PD-1, ICOS

TNF–TNFR
e.g. CD40, CD137, OX40

Cell adhesion molecules
e.g. CD2, LFA-1

CTLA4Ig
The blockage of CD28 using anti-CD28 monoclonal antibodies (mAbs) produces side effects and so a fusion protein, CTLA4Ig is used instead. CTLA4Ig is a hybrid of the extracellular region of CTLA4 and the Fc region of IgG1, and it competes with CD28 in binding to B7 on APCs, and so reduces T cell activation. CTLA4Ig (a.k.a. abatacept, trade name Orencia) has been approved for clinical use, and have prolonged allogragt survival in mice, although less so in non-human primates (NHP). A second generation of CTLA4Ig, belatacept, which differs from abatacept by 2 amino acids, is undergoing clinical trial, and has a higher affinity of binding, and so hopefully will perform better in NHPs.