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Review Article
Immunomodulatory Activity of DPP4
Mamgain S*, Mathur S and Kothiyal P
Department of Pharmaceutical Sciences, Shri Guru Ram Rai institute of Technology & Sciences, India

Dipeptidyle peptidase (DPP4) is the enzyme which is known to break down two gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) known as incretins effect. Beside this DPP4 plays potential role in modulating immune system. It causes proliferation of T cell by binding with adenosine diaminase (ADA) through co-stimulatory mechanism. Within immune system DPP4 exert mainly stimulating effect on T cells, B cells, natural killer cell ,DNA synthesis and release of TGFb. Evidence from experimental studies suggest the potential role of DPP4 in various inflammatory disease and increased risk of cancer .Inhibitor of DPP4 is novel treatment for diabetes mellitus type2 which inhibit DPP4.DPP4 plays crucial role in immune modulation therefore its prolong inhibition results in implication in immune system and increase risk of developing tumor. Therefore these classes of drugs prescribed with a caution. Further studies needed for more clarification.
Keywords
Dipeptidyle Peptidase 4; CD26; Immunomodulatory effect; ADA Co-stimulatory mechanism

INTRODUCTION
Dipeptidyle peptidase 4 (DPP-4) is the enzyme normally present in liver hepatocyte, kidney and intestine responsible for cleavage of glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) known as incretin effect.DPP4 shows immunomodulatory activity.DPP4 inhibitors are widely used for the treatment of type 2 diabetes mellitus by augmenting incretin signaling pathway [1]. Therefore long term inhibition of DPP-4 may play potential pathophysiological role in number of inflammatory disorders [2,3].
DPP 4 is also known as adenosine diaminase binding protein(ADBP) or T cell activation antigen CD26 [4]. It is 766 glycosylated multifunctional and is widely distributed serine protease it acts by cleaving the N terminal dipeptide after proline containing peptide. It act through various mechanism [5-7].
  • Proliferation of T cell by co- stimulation mechanism.
  • Involving in interaction with extracellular matrix.
  • Influencing proteolysis by activation and inactivation of many peptide lead to influence HIV, diabetes as well as immune system (Figure 1)
Figure 1 Flow chart.

Figure 1 Flow chart.

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DPP4 SUBSTRATE
DPP4 bind to several substrates which include Neuropeptide Y, Interleukins, incretin, cytokines, RANATES etc.
DPP4 in immune system
Experimental result from study of allogen bone marrow transplantation demonstrate decrease number of CD26 cell which involve in T cell proliferation through CD3 and CD2 pathway results in mature thymocyte similar to medullary thymocyte or cord T cell.DPP-4 ectopeptide present in plasma level of T lymphocyte and part of T lymphocyte characterize as memory T cell expressed on CD4 or CD8 hemopotein as well as on thymocyte B cell [8], cytokines [9]. It has been shown CD26 plays crucial role in T cell proliferation by co-stimulation mechanism. In addition CD26 also regarded as activation marker of B lymphocyte and natural killer cells [8]. Immunnoregulating cytokines part of immune system has been shown to substrate of DPP4 [3]. Hence DPP4 have major impact on immune system.
Adenosine diaminase (ADA) binding
Adenosine diaminase (ADA) catalyse deamination of adenosine to inosine in a purine catabolism pathway. ADA is ectoenzyme which synthesize by AMP dephosphrylation and taken by S-adenosylhomocysteine (SAH) to the extracellular space where it form complex with CD26 mediating the immune response through T cell activation.There are various forms of ADA,ADA1 bind to CD26 [10]. Neither adenosine activity nor enzymatic activity is required for binding of CD26 with ADA. ADA1 is isoform whose deficiency may associated with severe combined immunodeficiency (SCID).
ADA depend CD26 mediated signaling
ADA bind to its receptor [A2B] expressed on dendritic cell mediate T cell activation through co-stimulation by CD26.When ectoenzyme bound to its receptor A2B on dendritic cell results in increased cross linking of CD26.Cross linking of CD26 causes coprecipitation of CD26 and CD45RO on lipid rafts. Subsequently through interaction of CD26 with cytoplasmic domain d2 of CD45RO promote dephosphorylation of C terminal of regulatory domain of Src kinase such as Lck and Fyn activating them. Activated Lck bind to cytosolic domain of CD4 and CD8 and phosphorylates immunoreceptor tyrosine-based activation motif (ITAM) of CD3ζ allowing ZAP-70 (zeta chain associated protein kinase 70 normally expressed near the surface membrane of T cells) binding to phosphorylated ITAM. Thus Lck activate ZAP70. ZAP70 through phosphorylation of LAT promote activation of ERK pathway and PLCγ. The cross linking of ADA and CD26 induces a synergic effect on calcium mobilization triggered via the TCR/CD3 complex. Therefore, the co-stimulatory signal triggered via CD26-ADA interaction potentiates the TCR/CD3 engagement during the T cell activation.
The novel co-stimulatory intracellular interaction
Recently it has been discover that co-stimulatory effect through CD26 on T cell surface is promoted by ecto ADA colocalizing with A2B adenosine receptor expressed on antigen presenting cell (APC) surface. The novel co-stimulatory intracellular interaction involve in trimolecular interaction CD26, ADA and A2B receptor present on dendritic cell. Co-stimulation effect through cross linking of CD26 and ADA results in release of IL6, IFNγ and TNF α secretion [11].
LYMPHOCYTE
Presence of CD26 on B lymphocyte always has been controversial. A study using anti CD26 antibody recognize epitope of DPP4 indicating the presence of CD26 on T lymphocyte. According to experimental studies B cell expression was studied from healthy person and from patient of CVID (disease caused by B cell dysfunction). CD26 was detected with the help of specific enzyme substrate. After stimulation with pokeweed mitogen (PWM) or St auresis it shows the proliferation of CD26 nearly same. Treatment with DPP4 inhibitor on PWM and St auresis onstimulated B cell in a study shows DNA synthesis inhibition in dose dependent manner. All observation signifies DPP4 is not only activation marker of T cell and NK(natural killer) cell but also B cell [8].
CHEMOKINES
Stimulation of human T cell by pokeweed mitogen (PWM) shows decrease in mRNA expression of cytokinens [12]. Chemokinens related to cytokines plays role in chemotaxis phenomena (migration of T lymphocytes) exert it's signaling action through N terminal which is cleaved by CD26 results in impaired of signaling pathway in immune system. There are various type of cytokinines which involve in migration of esenophills on paracyte after processed by CD26 loses their ability to work in immune system. RANATES (regulated on activation normal T cell expressed and secreted) processed by CD26 become more than ten times lower in signaling binding on CCR1 and CCR3 result in lowering of chemotactic property. Stromal cell derived factor K present on surface of CXC chemokinines loses its efficacy due to manifestation in signaling pathway of CXC chemokinies. Cleavage of N terminal results in shorting of macrophage derived chemokinies which impaired its effect on Gly pro2 and Try3Gly4 leads to increase in substrate specificity as compared to before accepted for all. Therefore CD26 plays crucial role in transnucation of cytokinies involve in various immune regulating system. A study also shows DPP4 role in the production of IL2,IL6,IL10 and TNFα.
T LYMPHOCYTES
  • The main role of CD26 in T cell activation is determine by finding monoclonal antibodies against T cell activating agent results in release of interleukines and proliferation of CD4 and CD8 T cell.
  • IFN monoclonal antibody shows proliferation of CD26 which involve in cascade of reaction results in modulation of activated T cell.
  • CD45 is co precipitated with CD26 in T cell lysates.CD45 plays effective role in signaling T cell receptor and leads modulating effect of CD26.
  • The collagen bind activation of CD26 on T cell leads to produce co-stimulatory signal [13].
ROLE IN DNA SYNTHESIS AND TGFβ
CD26 plays crucial role in DNA synthesis evident by a study using phytohemaglutinin and Co-enzyme A stimulated assay. Inhibition of DPP4 results in release of TGF β may cause immune suppression. TGFβ is transforming growth factor β which involve in regulation and production of immune cell. Its release results in manifestation in immune system [14] (Figure 2).
Figure 2 Role of DPP4 in Various Immune Related Diseases.

Figure 2 Role of DPP4 in Various Immune Related Diseases.

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Table 1 Various substrate of DPP4.

SUBSTRATE

EFFECTS

Aprotinin

Inhibits trypsin and related proteolyic enzymes

Bradykinin

Causes vasodilates and increases vascular permeability

β – Casomorphin -2

Opioid - like effects on the CNS

Chromogranin

Modulates the neuroendocrine function

Endomorphin -2

Endogenous opioid - peptides

Eotaxin

( or CCL11) Chemotactive for eosinophils, implicated in asthma

GCP – 2

( or CXCL6) Recruits neutrophils

GHRH

Stimulates GH production and release by binding to the

GRP

Elicits gastrin release and regulates gastric acid secretion and motor function

IGF – 1

Allows childhood growth and anabolism in adults. Insulin counter - regulatory

Protactin

Allows lactation, regulate fertility and is counter - regulatory

IL – 2

Major role in specific immunity

IL - 1β

Major regulator of inflammation, cell proliferation, differentiation, apoptosis

IP – 10

( or CXCL10) Attracts leukocytes to the endothelium. Involved in bone marrow colony formation and angiogenesis

MCP - 1,- 2, - 3

( or CCL2) Recruits leukocytes to sites of tissue injury, infection, and inflammation

RANTES

( or CCL5) Recruits leukocytes into inflammatory sites

SDF- 1α, - 1β

Stimulates chemotaxis, stem / progenitor cell mobilization and homing

NPY

Regulation of energy balance, memory and learning

Substance P

Neuroransmitter and neuromodulator, role in neurogenic inflammation

PYY

Reduces appetite, inhibits gastric motility and increase water and electrolyte absorption in the colon

PHM

Causes vasodilates and possibly act as a neurotransmitter

GLP – 1

Promotes insulin secretion, slowing gastric emptying, reducing appetite

GLP – 2

Intestinal growth and function, reduction in bone resorption, neuroprotection

GIP

Inhibits GI motility and acid secretion. Stimulates insulin secretion and promotes fatty acid metabolism

Table 1 Various substrate of DPP4.

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HUMAN IMMUNE DEFICIENCY VIRUS
There were many hypothesis of CD26 associated with HIV in past but it is now confirmed by study that CD26+ cell are more sensitive towards HIV infection in comparison to CD26- cells. CD26 interact with TAT protein which is trans activated HIV protein. Sialylation of CD26 indicates its interaction with TAT protein and Hypersialylation of CD26 contributes to the fusion of HIV particle with its host.TAT protein on interaction with CD26 inhibit DPP4 mediated T cell proliferation through co-stimulation result in diminishing immune response.
Another is gp120 an envelope glycoprotein protein of HIV particle interact with CD26 through C3 region while interact with CD4 through V3 loop results in loss of binding of ADA to CD26 affecting immune response. High level of ADA found in HIV infected patient. Beside these two protein chemokines plays role in HIV [15]. RANATES is known to inhibit HIV infection via its capability of binding with CCR5.RANATES processed by CD26 is compared with intact RANATES with macrophage tropic activity ound processed RANATES are more effective against HIV1.In early stage of HIV highly expressed CD26 would be beneficial because of M tropic CCR5. In later stage of HIV infected patient CD26 diminish immune response and enabling person more susceptible for HIV due to abolish protective effect of SDF(stromal cell derived factor)1α [13].
Table 2 Tissue distribution of human CD26.

ORGAN

CD26+ CELLS

Kidney

Proximal tubule epithelium,glomerulus endothelia

Liver

Bile canaculi,bile duct epithelia

Skin

Fibrocytes

Parotid gland

Acinus epithelia

Spleen

Sinus-lining cell

Adrenal gland

Zone reticularis

Prostate gland

Epithelia

Lungs

Endothelia

Table 2 Tissue distribution of human CD26..

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CANCER
The relation of DPP4 to cancer biology is extreamely complex and has been repeatedly reviewed recently.DPP4 regulate apoptosis, immune regulation, antiproliferative and anticogenic action for cancerous cell thereby modulating development of cancer. Several studies evident downregulation of DPP4 in ovarian cancer, which resulting in increase of ductal cell turnover and inducing ductal mataplase by intacting β cell and its function. DPP4 inhibitor Sitagliptin may contribute to pancreatic cancer. Sitagliptin use in the treatment diabetes mellitus type 2 act by inhibiting action of DPP4 which causes cleavage of GLP2. GLP2 have proliferative effect on intestinal cell. Therefore DPP4 inhibition exerted tumor promoting effect on intestinal cancer cell invitro [3].
Acute allograft rejection
CD26 shown to decrease immune suppression investigated in TX cardiac recipient patient by using DPP4 inhibitor. DPP4 inhibitor prolong TX cardiac recipient survival which signify role of CD26 in immune regulation [16].
Inflammatory bowel disease
Inflammatory bowel disease caused by increase in number of inflammatory cell [17]. Role of DPP4 in IBD is define by investigation supporting high expression of CD26 on T lymphocyte as compared to control. In laboratory dextran sulphate sodium induced colitis in DPP+/+ and DPP4-/-. DPP4-/- mice shows to exaggerate inflammatory response as compared to DPP+/+ mice. IBD and colitis can be use as in vivo model for evaluating immune modulatory activity of DPP4 [18].
Rheumatoid arthritis
Rheumatoid arthritis is a disease caused by increase in a number of lymphocyte in synovial fluid. Role of DPP4 is investigated by using two animal model of Rheumatoid arthritis
1) Collagen induced arthritis
2) Alkyldiamine induced arthritis
DPP4 inhibitor shows anti arthritic effect by suppressing collagen induced arthritis as well as alkyldiamine arthritis indicating role of DPP4 in immune regulation [19]. Specific serum activity of DPP4 is decrease in Rheumatoid arthritis patients [20].
Depression
A study of DPP4 inhibitor demonstrate the role of DPP4 in depression shows that
  • Major depression is associated with decrease level of DPP4
  • Antidepressant does not have any effect on DPP4 activity
  • Low DPP4 serum level is important marker in depression [21].
Angiodema
Angiodema is a disease caused by swelling of skin, mucous membrane or both including upper respiratory and intestinal epithelial linings. It is caused by increase in permeability of subcutaneous capillaries which leads to extravasation of plasma and ephemeral swelling [22]. ACE (Angiotensin converting enzyme) plays a primary role in degradation of Bradykinin which results in increased vascular permeability which in turn causes Angiodema. Use of ACE inhibitor results in decreased degradation of Bradykinin but DPP4 secondary pathway increases its degradation. DPP4 inhibitor along with ACE inhibitor results in decrease in degradation of Bradykinin which causes Angiodema. For study purposes one patient of RA on immunosuppressant drugs along with two patients from heart transplantation and one patient with history of malignancy forma comprehensive study group. Angiodema is found to be associated with malignancy as well as in autoimmune disorder [23].
Multiple sclerosis
Multiple sclerosis is demethylating disease caused by abrupt activation of immune system [24]. In multiple sclerosis activated CD4,Th1 and various cytokines are found on myelin based protein (MBP).A study shows that CD26 present on myelin based protein,CD4 and T cell clones plays important role in regulation of T cell clones. Hence DPP4 inhibitor is found to be effective in treatment of multiple sclerosis and it can serve as in vivo model for DPP4 inhibitor [25].
Evidence from preclinical and clinical studies
DPP4 is widely expressed on kidney,liver,small intestine and blood cell of rat.DPP4 activity is determined by using DPP4 inhibitor in invitro studies which substantiated inhibition in T cell proliferation whereas invivo studies using Bovine Serum Albumin(BSA) with DPP4 inhibitor has shown to decrease level of antibody formation followed by decrease in serum enzymatic activity of DPP4 [26].
Hepatitis is one of the infectious disease for which vaccine is available but sometimes incompetence of vaccine is seen in a person due to low level of antibody after vaccination CD26/DPP4 increase T cell proliferation while increasing serum level of DPP4 at the same time [27]. After hepatitis B vaccine the serum level of DPP4 found to increased level of CD45 (which is classic marker of T cell activation) in responder patient [10].
CONCLUSION
Although both pre-clinical and clinical studies have shown potential role of DPP4 therapy in diabetes but beyond DPP4 effect in regulation of energy homeostasis, itsrole in various immune related disorders has been implicated. Various experimental findings have suggested the role of DPP4 in T cell, B cell and natural killer cell activation. Despite this there is increased risk of tumors after prolonged use of DPP4 inhibitors as indicated by experimental studies. Therefore DPP4 inhibitors in clinical practice are still in question because of the safety issue. Based on above stated arguments we can aver that more statistics be collected and studied before starting human testing.
FUTURE PROSPECTS
Further studies are needed for more clarification about role of DPP4 in immune response to protect dangerous effect of using DPP4 inhibitor and hence should be given with some degree of caution in patient to safeguard their lives.

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Cite this article: Mamgain S, Mathur S, Kothiyal P (2013) Immunomodulatory Activity of DPP4. J Pharmacol Clin Toxicol 1(1): 1006.
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